TETRAHYDRO- PYRIDO[3,4- b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF

ABSTRACT

Described herein are tetrahydro-pyrido[3,4-b]indol-1-yl compounds with estrogen receptor modulation activity or function having the Formula I structure:and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such estrogen receptor modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application filed under 37 CFR § 1.53(b), claimsthe benefit under 35 USC § 119(e) of U.S. Provisional Application Ser.No. 62/093,929 filed on 18 Dec. 2014, U.S. Provisional Application Ser.No. 62/110,998 filed on 2 Feb. 2015, and U.S. Provisional ApplicationSer. No. 62/142,077 filed on 2 Apr. 2015, which are incorporated byreference in their entirety.

FIELD OF THE INVENTION

Described herein are compounds, including pharmaceutically acceptablesalts, solvates, metabolites, prodrugs thereof, pharmaceuticalcompositions comprising such compounds, and methods of using suchcompounds to treat, prevent or diagnose diseases or conditions that areestrogen sensitive, estrogen receptor dependent or estrogen receptormediated in combination with other therapeutic agents.

BACKGROUND OF THE INVENTION

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with endogenous estrogens. Endogenousestrogens include 17β (beta)-estradiol and estrones. ER has been foundto have two isoforms, ER-α (alpha) and ER-β (beta). Estrogens andestrogen receptors are implicated in a number of diseases or conditions,such as breast cancer, lung cancer, ovarian cancer, colon cancer,prostate cancer, endometrial cancer, uterine cancer, as well as othersdiseases or conditions. There is a need for new ER-α targeting agentsthat have activity in the setting of metastatic disease and acquiredresistance.

SUMMARY OF THE INVENTION

The invention relates generally to tetrahydro-pyrido[3,4-b]indol-1-ylcompounds with estrogen receptor modulation activity or function havingthe Formula I structure:

and stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, and with the substituents and structural features describedherein.

An aspect of the invention is a pharmaceutical composition of a FormulaI compound and a pharmaceutically acceptable carrier, glidant, diluent,or excipient.

An aspect of the invention is a process for making a Formula I compoundor a pharmaceutical composition comprising a Formula I compound.

An aspect of the invention is a method of treating an ER-related diseaseor disorder in a patient comprising administering a therapeuticallyeffective amount of the pharmaceutical composition to a patient with anER-related disease or disorder.

An aspect of the invention is a kit for treating a condition mediated byan estrogen receptor, comprising:

a) a pharmaceutical composition comprising a Formula I compound; and

b) instructions for use.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety. The nomenclature used in this Application is based on IUPACsystematic nomenclature, unless indicated otherwise.

Definitions

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents. The term “substituent” denotes an atom ora group of atoms replacing a hydrogen atom on the parent molecule. Theterm “substituted” denotes that a specified group bears one or moresubstituents. Where any group may carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating thenumber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. In anotherembodiment, an alkyl radical is one to eight carbon atoms (C₁-C₈), orone to six carbon atoms (C₁-C₆). Examples of alkyl groups include, butare not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkyldiyl” as used herein refers to a saturated linear orbranched-chain divalent hydrocarbon radical of about one to twelvecarbon atoms (C₁-C₁₂), wherein the alkyldiyl radical may be optionallysubstituted independently with one or more substituents described below.In another embodiment, an alkyldiyl radical is one to eight carbon atoms(C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkyldiylgroups include, but are not limited to, methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), and the like. An alkyldiyl groupmay also be referred to as an “alkylene” group.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and the like.

The terms “alkenylene” or “alkenyldiyl” refer to a linear orbranched-chain divalent hydrocarbon radical of two to eight carbon atoms(C₂-C₈) with at least one site of unsaturation, i.e., a carbon-carbon,sp² double bond, wherein the alkenylene radical may be optionallysubstituted independently with one or more substituents describedherein, and includes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. Examples include, but are notlimited to, ethylenylene or vinylene (—CH═CH—), allyl (—CH₂CH═CH—), andthe like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to eight carbon atoms (C₂-C₈) with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH), and the like.

The term “alkynylene” or “alkynyldiyl” refer to a linear or brancheddivalent hydrocarbon radical of two to eight carbon atoms (C₂-C₈) withat least one site of unsaturation, i.e., a carbon-carbon, sp triplebond, wherein the alkynylene radical may be optionally substitutedindependently with one or more substituents described herein. Examplesinclude, but are not limited to, ethynylene (—C≡C—), propynylene(propargylene, —CH₂C≡C—), and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as a monocyclicring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or asbridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Spiro carbocyclyl moieties are also includedwithin the scope of this definition. Examples of spiro carbocyclylmoieties include [2.2]pentanyl, [2.3]hexanyl, and [2.4]heptanyl.Examples of monocyclic carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and thelike. Carbocyclyl groups are optionally substituted independently withone or more substituents described herein.

The term “carbocyclyldiyl” refers to a divalent non-aromatic, saturatedor partially unsaturated ring having 3 to 12 carbon atoms (C₁-C₁₂) as amonocyclic ring or 7 to 12 carbon atoms as a bicyclic ring.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein.

The terms “arylene” or “aryldiyl” mean a divalent aromatic hydrocarbonradical of 6-20 carbon atoms (C₆-C₂₀) derived by the removal of twohydrogen atom from a two carbon atoms of a parent aromatic ring system.Some aryldiyl groups are represented in the exemplary structures as“Ar”. Aryldiyl includes bicyclic radicals comprising an aromatic ringfused to a saturated, partially unsaturated ring, or aromaticcarbocyclic ring. Typical aryldiyl groups include, but are not limitedto, radicals derived from benzene (phenyldiyl), substituted benzenes,naphthalene, anthracene, biphenylene, indenylene, indanylene,1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.Aryldiyl groups are also referred to as “arylene”, and are optionallysubstituted with one or more substituents described herein.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to about 20 ring atoms in which atleast one ring atom is a heteroatom selected from nitrogen, oxygen,phosphorus and sulfur, the remaining ring atoms being C, where one ormore ring atoms is optionally substituted independently with one or moresubstituents described below. A heterocycle may be a monocycle having 3to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selectedfrom N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), forexample: a bicyclo [4,5], [5,5], [5,6], or [6,6] system. Heterocyclesare described in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)82:5566. “Heterocyclyl” also includes radicals where heterocycleradicals are fused with a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but are not limited to, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro heterocyclyl moieties are alsoincluded within the scope of this definition. Examples of spiroheterocyclyl moieties include azaspiro[2.5]octanyl andazaspiro[2.4]heptanyl. Examples of a heterocyclic group wherein 2 ringatoms are substituted with oxo (═O) moieties are pyrimidinonyl and1,1-dioxo-thiomorpholinyl. The heterocycle groups herein are optionallysubstituted independently with one or more substituents describedherein.

The term “heterocyclyldiyl” refers to a divalent, saturated or apartially unsaturated (i.e., having one or more double and/or triplebonds within the ring) carbocyclic radical of 3 to about 20 ring atomsin which at least one ring atom is a heteroatom selected from nitrogen,oxygen, phosphorus and sulfur, the remaining ring atoms being C, whereone or more ring atoms is optionally substituted independently with oneor more substituents as described.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups areoptionally substituted independently with one or more substituentsdescribed herein.

The term “heteroaryldiyl” refers to a divalent aromatic radical of 5-,6-, or 7-membered rings, and includes fused ring systems (at least oneof which is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), ornitrogen (nitrogen-linked) bonded where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The terms “treat” and “treatment” refer to therapeutic treatment,wherein the object is to slow down (lessen) an undesired physiologicalchange or disorder, such as the development or spread of arthritis orcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment. Those in need of treatment include those with the conditionor disorder.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats the particulardisease, condition, or disorder, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease, condition, ordisorder, or (iii) prevents or delays the onset of one or more symptomsof the particular disease, condition, or disorder described herein. Inthe case of cancer, the therapeutically effective amount of the drug mayreduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,slow to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; and/orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth and/or kill existingcancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy,efficacy can be measured, for example, by assessing the time to diseaseprogression (TTP) and/or determining the response rate (RR).

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

“Hematological malignancies” (British spelling “Haematological”malignancies) are the types of cancer that affect blood, bone marrow,and lymph nodes. As the three are intimately connected through theimmune system, a disease affecting one of the three will often affectthe others as well: although lymphoma is a disease of the lymph nodes,it often spreads to the bone marrow, affecting the blood. Hematologicalmalignancies are malignant neoplasms (“cancer”), and they are generallytreated by specialists in hematology and/or oncology. In some centers“Hematology/oncology” is a single subspecialty of internal medicinewhile in others they are considered separate divisions (there are alsosurgical and radiation oncologists). Not all hematological disorders aremalignant (“cancerous”); these other blood conditions may also bemanaged by a hematologist. Hematological malignancies may derive fromeither of the two major blood cell lineages: myeloid and lymphoid celllines. The myeloid cell line normally produces granulocytes,erythrocytes, thrombocytes, macrophages and mast cells; the lymphoidcell line produces B, T, NK and plasma cells. Lymphomas, lymphocyticleukemias, and myeloma are from the lymphoid line, while acute andchronic myelogenous leukemia, myelodysplastic syndromes andmyeloproliferative diseases are myeloid in origin. Leukemias includeAcute lymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML),Chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML),Acute monocytic leukemia (AMOL) and small lymphocytic lymphoma (SLL).Lymphomas include Hodgkin's lymphomas (all four subtypes) andNon-Hodgkin's lymphomas (NHL, all subtypes).

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkylatingagents, antimetabolites, spindle poison plant alkaloids,cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: ibrutinib (IMBRUVICA™,APCI-32765, Pharmacyclics Inc./Janssen Biotech Inc.; CAS Reg. No.936563-96-1, U.S. Pat. No. 7,514,444), idelalisib (ZYDELIG®, CAL-101, GS1101, GS-1101, Gilead Sciences Inc.; CAS Reg. No. 1146702-54-6),erlotinib (TARCEVA®, Genentech/OSI Pharm.), docetaxel (TAXOTERE®,Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS Reg. No.51-21-8), gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9,Pfizer), cisplatin (Platinol®, (SP-4-2)-diamminedichloroplatinum(II),cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CASNo. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide,CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®, CAS No.23214-92-8), Akti-1/2, HPPD, and rapamycin.

Chemotherapeutic agents include inhibitors of B-cell receptor targetssuch as BTK, Bcl-2 and JAK inhibitors.

More examples of chemotherapeutic agents include; oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, 11),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chlorambucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlomaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem.Inti. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, carminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylomithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of “chemotherapeutic agent” are; (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxy tamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate) and selective estrogen receptor modulators (SERDs) such asfulvestrant (FASLODEX®, Astra Zeneca); (ii) aromatase inhibitors thatinhibit the enzyme aromatase, which regulates estrogen production in theadrenal glands, such as, for example, 4(5)-imidazoles,aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane;Pfizer), formestanie, fadrozde, RIVISOR® (vorozole), FEMARA® (letrozole;Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii)anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide,and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleosidecytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors,such as cobimetinib (WO 2007/044515); (v) lipid kinase inhibitors, suchas taselisib (GDC-0032, Genentech Inc.); (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, forexample, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSE®, GentaInc.); (vii) ribozymes such as VEGF expression inhibitors (e.g.,ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as genetherapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®;PROLEUKIN® rTL-2; topoisomerase 1 inhibitors such as LURTOTECAN®;ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab(AVASTIN®, Genentech); and pharmaceutically acceptable salts, acids andderivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (PERJETA™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), trastuzumab emtansine (KADCYLA®, Genentech Inc.), andtositumomab (BEXXAR, Corixia).

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of theinvention, including compounds produced by a process comprisingcontacting a Formula I compound of this invention with a mammal for aperiod of time sufficient to yield a metabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral centers). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity. Enantiomers may be separated from a racemic mixture bya chiral separation method, such as supercritical fluid chromatography(SFC). Assignment of configuration at chiral centers in separatedenantiomers may be tentative, and depicted in Table 1 structures forillustrative purposes, while stereochemistry is definitivelyestablished, such as from x-ray crystallographic data.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The term “pharmaceutically acceptable salts” denotes salts which are notbiologically or otherwise undesirable. Pharmaceutically acceptable saltsinclude both acid and base addition salts. The phrase “pharmaceuticallyacceptable” indicates that the substance or composition must becompatible chemically and/or toxicologically, with the other ingredientscomprising a formulation, and/or the mammal being treated therewith.

The term “pharmaceutically acceptable acid addition salt” denotes thosepharmaceutically acceptable salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid, and organic acids selected fromaliphatic, cycloaliphatic, aromatic, aryl-aliphatic, heterocyclic,carboxylic, and sulfonic classes of organic acids such as formic acid,acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid,ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamicacid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonicacid “mesylate”, ethanesulfonic acid, p-toluenesulfonic acid, andsalicyclic acid.

The term “pharmaceutically acceptable base addition salt” denotes thosepharmaceutically acceptable salts formed with an organic or inorganicbase. Examples of acceptable inorganic bases include sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Salts derived from pharmaceutically acceptable organicnontoxic bases includes salts of primary, secondary, and tertiaryamines, substituted amines including naturally occurring substitutedamines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, and polyamine resins

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethylacetate (EtOAc), acetic acid (AcOH), andethanolamine.

The term “EC₅₀” is the half maximal effective concentration” and denotesthe plasma concentration of a particular compound required for obtaining50% of the maximum of a particular effect in vivo.

The term “Ki” is the inhibition constant and denotes the absolutebinding affinity of a particular inhibitor to a receptor. It is measuredusing competition binding assays and is equal to the concentration wherethe particular inhibitor would occupy 50% of the receptors if nocompeting ligand (e.g. a radioligand) was present. Ki values can beconverted logarithmically to pKi values (−log Ki), in which highervalues indicate exponentially greater potency.

The term “IC₅₀” is the half maximal inhibitory concentration and denotesthe concentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC₅₀ values can beconverted logarithmically to pIC₅₀ values (−log IC₅₀), in which highervalues indicate exponentially greater potency. The IC₅₀ value is not anabsolute value but depends on experimental conditions e.g.concentrations employed, and can be converted to an absolute inhibitionconstant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol.(1973) 22:3099). Other percent inhibition parameters, such as IC₇₀,IC₉₀, etc., may be calculated.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula I” include compounds of Formulas Iand stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts and prodrugs thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to 2H(deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 3 IP, 32P, 35S,360, and 1251. Various isotopically labeled compounds of the presentinvention, for example those into which radioactive isotopes such as 3H,13C, and 14C are incorporated. Such isotopically labeled compounds maybe useful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. Deuterium labeled or substituted therapeutic compounds of theinvention may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism, and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An18F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., 2H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the formula(I). The concentration of such a heavier isotope, specificallydeuterium, may be defined by an isotopic enrichment factor. In thecompounds of this invention any atom not specifically designated as aparticular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Accordingly, inthe compounds of this invention any atom specifically designated as adeuterium (D) is meant to represent deuterium.

Estrogen Receptor

Estrogen receptor alpha (ER-α; NR3A1) and estrogen receptor beta (ER-β;NR3A2) are steroid hormone receptors, which are members of the largenuclear receptor superfamily. Nuclear receptors share a common modularstructure, which minimally includes a DNA binding domain (DBD) and aligand binding domain (LBD). Steroid hormone receptors are soluble,intracellular proteins that act as ligand-regulated transcriptionfactors. Vertebrates contain five closely related steroid hormonereceptors (estrogen receptor, androgen receptor, progesterone receptor,glucocorticoid receptor, mineralcorticoid receptor), which regulate awide spectrum of reproductive, metabolic and developmental activities.The activities of ER are controlled by the binding of endogenousestrogens, including 17 β-estradiol and estrones.

The ER-α (alpha) gene is located on 6q25.1 and encodes a 595 AA protein.The ER-β gene resides on chromosome 14q23.3 and produces a 530 AAprotein. However, due to alternative splicing and translation startsites, each of these genes can give rise to multiple isoforms. Inaddition to the DNA binding domain (called C domain) and ligand bindingdomain (E domain) these receptors contain an N-terminal (A/B) domain, ahinge (D) domain that links the C and E domains, and a C-terminalextension (F domain) (Gronemeyer and Laudet; Protein Profile 2:1173-1308, 1995). While the C and E domains of ER-α and ER-β are quiteconserved (95% and 55% amino acid identity, respectively), conservationof the A/B, D and F domains is poor (below 30% amino acid identity).Both receptors are involved in the regulation and development of thefemale reproductive tract but also play various roles in the centralnervous system, cardiovascular systems and bone metabolism.

The ligand binding pocket of steroid hormone receptors is deeply buriedwithin the ligand binding domain. Upon binding, the ligand becomes partof the hydrophobic core of this domain. Consequently most steroidhormone receptors are instable in the absence of hormone and requireassistance from chaperones, such as Hsp90, in order to maintainhormone-binding competency. The interaction with Hsp90 also controlsnuclear translocation of these receptors. Ligand-binding stabilizes thereceptor and initiates sequential conformational changes that releasethe chaperones, alter the interactions between the various receptordomains and remodel protein interaction surfaces that allow thesereceptors to translocate into the nucleus, bind DNA and engage ininteractions with chromatin remodeling complexes and the transcriptionalmachinery. Although ER can interact with Hsp90, this interaction is notrequired for hormone binding and, dependent on the cellular context,apo-ER can be both cytoplasmic and nuclear. Biophysical studiesindicated that DNA binding rather than ligand binding contributes to thestability of the receptor (Greenfield et al., Biochemistry 40:6646-6652, 2001).

ER can interact with DNA either directly by binding to a specific DNAsequence motif called estrogen response element (ERE) (classicalpathway), or indirectly via protein-protein interactions (nonclassicalpathway) (Welboren et al., Endocrine-Related Cancer 16: 1073-1089,2009). In the nonclassical pathway, ER has been shown to tether to othertranscription factors including SP-1, AP-1 and NF-κB. These interactionsappear to play critical roles in the ability of ER to regulate cellproliferation and differentiation.

Both types of ER DNA interactions can result in gene activation orrepression dependent on the transcriptional coregulators that arerecruited by the respective ER-ERE complex (Klinge, Steroid 65: 227-251,2000). The recruitment of coregulators is primarily mediated by twoprotein interaction surfaces, the AF2 and AF1. AF2 is located in the ERE-domain and its conformation is directly regulated by the ligand(Brzozowski et al., (1997) Nature 389: 753-758,). Full agonists appearto promote the recruitment of co-activators, whereas weak agonists andantagonists facilitate the binding of co-repressors. The regulation ofprotein with the AF1 is less well understood but can be controlled byserine phosphorylation (Ward and Weigel, (2009) Biofactors 35: 528-536).One of the involved phosphorylation sites (SI 18) appears to control thetranscriptional activity of ER in the presence of antagonists such astamoxifen, which plays an important role in the treatment of breastcancer. While full agonists appear to arrest ER in certain conformation,weak agonists tend to maintain ER in equilibrium between differentconformations, allowing cell-dependent differences in co-regulatorrepertoires to modulate the activity of ER in a cell-dependent manner(Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). Interactions ofER with DNA are dynamic and include, but are not limited to, thedegradation of ER by the proteasome (Reid et al., Mol Cell 11: 695-707,2003). The degradation of ER with ligands provides an attractivetreatment strategy for diseases or conditions that areestrogen-sensitive and/or resistant to available anti-hormonaltreatments. ER signaling is crucial for the development and maintenanceof female reproductive organs including breasts, ovulation andthickening of the endometrium. GR signaling also has a role in bonemass, lipid metabolism, cancers, etc. About 70% of breast cancersexpress ER-D (ER-D positive) and are dependent on estrogens for growthand survival. Other cancers also are thought to be dependent on ER-αsignaling for growth and survival, such as for example ovarian andendometrial cancers. The ER-α antagonist tamoxifen has been used totreat early and advanced ER-α positive breast cancer in both pre- andpost-menopausal women. Fulvestrant (FASLODEX®, AstraZeneca) asteroid-based ER antagonist is used to treat breast cancer in womenwhich have progressed despite therapy with tamoxifen (Howell A. (2006)Endocr Relat Cancer; 13:689-706; U.S. Pat. Nos. 6,774,122; 7,456,160;8,329,680; 8,466,139). Steroidal and non-steroidal aromatase inhibitorsare also used to treat cancers in humans. In some embodiments, thesteroidal and non-steroidal aromatase inhibitors block the production ofestrogen from androstenedione and testosterone in post-menopausal women,thereby blocking ER dependent growth in the cancers. In addition tothese anti-hormonal agents, progressive ER positive breast cancer istreated in some cases with a variety of other chemotherapeutics, such asfor example, the anthracylines, platins, taxanes. In some cases, ERpositive breast cancers that harbor genetic amplification of theERB-B/HER2 tyrosine kinase receptor are treated with the monoclonalantibody trastuzumab (Herceptin®, Genentech Inc.) or the small moleculepan-ERB-B inhibitor lapatinib (TYKERB®, GlaxoSmith Kline Corp.). Despitethis battery of anti-hormonal, chemotherapeutic and small-molecule andantibody-based targeted therapies, many women with ER-α positive breastdevelop progressive metastatic disease and are in need of new therapies.Importantly, the majority of ER positive tumors that progress onexisting anti-hormonal, as well as and other therapies, are thought toremain dependent on ER-α for growth and survival. Thus, there is a needfor new ER-α targeting agents that have activity in the setting ofmetastatic disease and acquired resistance. In one aspect, describedherein are compounds that are selective estrogen receptor modulators(SERMs). In specific embodiments, the SERMs described herein areselective estrogen receptor degraders (SERDs). In some embodiments, incell-based assays the compounds described herein result in a reductionin steady state ER-α levels (i.e. ER degradation) and are useful in thetreatment of estrogen sensitive diseases or conditions and/or diseasesor conditions that have developed resistant to anti-hormonal therapies.

Most breast cancer patients are treated with agents that either blockestrogen synthesis (e.g., aromatase inhibitors; AIs) or antagonize theeffects of estradiol via competitive ER binding (e.g., tamoxifen)(Puhalla S, et al Mol Oncol 2012; 6(2):222-236). Despite the welldocumented therapeutic utility of these agents in various stages ofdisease, many ER+ breast cancers recur and patients eventually succumb.Recently, next generation whole genome and targeted sequencing hasidentified ESR1(estrogen receptor alpha gene) mutations in up to 20% oftumors from patients with advanced breast cancer who have progressed onendocrine therapies, largely aromatase inhibitors (Li S, et al. Cell Rep(2013); 4(6): 1116-1130; Merenbakh-Lamin K, et al. Cancer Res (2013);73(23): 6856-6864; Robinson D R, et al. Nat Genet (2013); 45(12):1446-1451; Toy W, et al. Nat Genet (2013); 45(12): 1439-1445; JeselsohnR, et al. Clin Cancer Res (2014); 20: 1757-1767). These ligand-bindingdomain (LBD) mutations confer high basal activity of the apo-receptorrendering them ligand-independent and thus active in the setting of lowestradiol. There is a need for therapies that target ER signaling withrobust activity in the setting of progressive disease post AT ortamoxifen treatment including the subset of patients harboring ESR1mutant tumors.

In some embodiments, Formula I compounds disclosed herein are used inmethods for treating a hormone resistant-estrogen receptor (ER) positivebreast cancer in a patient characterized as having a mutation in theESR1 gene, comprising administering a therapeutically-effective amountof a Formula I compound. In some embodiments, the mutation in the ESR1gene results in an ER polypeptide having an amino acid substitution at aposition selected from among amino acids positions 6, 118, 269, 311,341, 350, 380, 392, 394, 433, 463, 503, 534, 535, 536, 537, 538 and 555of SEQ ID NO:2. In some embodiments, the mutation results in an ERpolypeptide having an amino acid substitution selected from among H6Y,S118P, R269C, T311M, S341L, A350E, E380Q, V392I, R394H, S433P, S463P,R503W, V534E, P535H, L536R, L536P, L536Q, Y537N, Y537C, Y537S, D538G,and R555C. In some embodiments, the patient has two or more mutations inthe ESR1 gene.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agents that canmodulate other critical pathways in breast cancer, including but notlimited to those that target IGF1R, EGFR, CDK 4/6, erB-B2 and 3, thePI3K/AKT/mTOR axis, HSP90, PARP or histone deacetylases.

Given the central role of ER-α in breast cancer development andprogression, Formula I compounds disclosed herein are useful in thetreatment of breast cancer, either alone or in combination with otheragent used to treat breast cancer, including but not limited toaromatase inhibitors, anthracyclines, platins, nitrogen mustardalkylating agents, taxanes. Illustrative agent used to treat breastcancer, include, but are not limited to, PI3K inhibitors such astaselisib (GDC-0032, Genentech Inc.), paclitaxel, anastrozole,exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole(FEMARA®, Novartis, Corp.), gemcitabine, trastuzumab, pegfilgrastim,filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine(XELODA®, Roche), ixabepilone, as well as others described herein.

ER-related diseases or conditions include ER-α dysfunction is associatedwith cancer (bone cancer, breast cancer, lung cancer, colorectal cancer,endometrial cancer, prostate cancer, ovarian and uterine cancer),central nervous system (CNS) defects (alcoholism, migraine),cardiovascular system defects (aortic aneurysm, susceptibility tomyocardial infarction, aortic valve sclerosis, cardiovascular disease,coronary artery disease, hypertension), hematological system defects(deep vein thrombosis), immune and inflammation diseases (Graves'Disease, arthritis, multiple sclerosis, cirrhosis), susceptibility toinfection (hepatitis B, chronic liver disease), metabolic defects (bonedensity, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis), neurological defects (Alzheimer's disease, Parkinson'sdisease, migraine, vertigo), psychiatric defects (anorexia nervosa,attention deficit hyperactivity disorder (ADHD), dementia, majordepressive disorder, psychosis) and reproductive defects (age ofmenarche, endometriosis, infertility.

In some embodiments, compounds disclosed herein are used in thetreatment of an estrogen receptor dependent or estrogen receptormediated disease or condition in mammal.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal. In some embodiments, the cancer is breast cancer, ovariancancer, endometrial cancer, prostate cancer, or uterine cancer. In someembodiments, the cancer is breast cancer, lung cancer, ovarian cancer,endometrial cancer, prostate cancer, or uterine cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecancer is a hormone dependent cancer. In some embodiments, the cancer isan estrogen receptor dependent cancer. In some embodiments, the canceris an estrogen-sensitive cancer. In some embodiments, the cancer isresistant to anti-hormonal treatment. In some embodiments, the cancer isan estrogen-sensitive cancer or an estrogen receptor dependent cancerthat is resistant to anti-hormonal treatment. In some embodiments, thecancer is a hormone-sensitive cancer or a hormone receptor dependentcancer that is resistant to anti-hormonal treatment. In someembodiments, anti-hormonal treatment includes treatment with at leastone agent selected from tamoxifen, fulvestrant, steroidal aromataseinhibitors, and non-steroidal aromatase inhibitors.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, compounds disclosed herein are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal. In some embodiments, the benign ormalignant disease is breast cancer.

In some embodiments, the compound used in any of the methods describedherein is an estrogen receptor degrader; is an estrogen receptorantagonist; has minimal or negligible estrogen receptor agonistactivity; or combinations thereof.

In some embodiments, methods of treatment with compounds describedherein include a treatment regimen that includes administering radiationtherapy to the mammal.

In some embodiments, methods of treatment with compounds describedherein include administering the compound prior to or following surgery.

In some embodiments, methods of treatment with compounds describedherein include administering to the mammal at least one additionalanti-cancer agent.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is chemotherapy-naive.

In some embodiments, compounds disclosed herein are used in thetreatment of cancer in a mammal. In some embodiments, compoundsdisclosed herein are used to treat cancer in a mammal, wherein themammal is being treated for cancer with at least one anti-cancer agent.In one embodiment, the cancer is a hormone refractory cancer.

In some embodiments, compounds disclosed herein are used in thetreatment or prevention of diseases or conditions of the uterus in amammal. In some embodiments, the disease or condition of the uterus isleiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis.In some embodiments, the disease or condition of the uterus is acancerous disease or condition of the uterus. In some other embodiments,the disease or condition of the uterus is a non-cancerous disease orcondition of the uterus.

In some embodiments, compounds disclosed herein are used in thetreatment of endometriosis in a mammal.

In some embodiments, compounds disclosed herein are used in thetreatment of leiomyoma in a mammal. In some embodiments, the leiomyomais a uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma, orsmall bowel leiomyoma. In some embodiments, compounds disclosed hereinare used in the treatment of fibroids in a mammal.

In some embodiments, compounds disclosed herein are used in thetreatment of uterine fibroids in a mammal.

Tetrahydro-pyrido[3,4-b]indol-1-yl Compounds

The present invention provides tetrahydro-pyrido[3,4-b]indol-1-ylcompounds of Formula I, including Formulas Ia-If, and pharmaceuticalformulations thereof, which are potentially useful in the treatment ofdiseases, conditions and/or disorders modulated by Estrogen Receptoralpha (ERa).

Formula I compounds have the structure:

and stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein:

Y¹ is CR^(b) or N;

Y² is —(CH₂)—, —(CH₂CH₂)— or NR^(a);

Y³ is NR^(a) or C(R^(b))₂;

where one of Y¹, Y² and Y³ is N or NR^(a);

R^(a) is selected from H, C₁-C₆ alkyl, C₂-C₈ alkenyl, propargyl, C₃-C₆cycloalkyl, and C₃-C₆ heterocyclyl, optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, OH, OCH₃, andSO₂CH₃;

R^(b) is independently selected from H, —O(C₁-C₃ alkyl), C₁-C₆ alkyl,C₂-C₈ alkenyl, propargyl, —(C₁-C₆ alkyldiyl)-(C₃-C₆ cycloalkyl), C₃-C₆cycloalkyl, and C₃-C₆ heterocyclyl, optionally substituted with one ormore groups independently selected from F, Cl, Br, I, CN, —CH₂F, —CHF₂,—CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, OH, OCH₃, and SO₂CH₃;

R^(c) is selected from H, C₁-C₆ alkyl, allyl, propargyl, optionallysubstituted with one or more groups independently selected from F, Cl,Br, I, CN, OH, OCH₃, and SO₂CH₃;

Z¹ is selected from CR^(a)R^(b), C(O), and a bond;

Cy is selected from C₆-C₂₀ aryldiyl, C₃-C₁₂ carbocyclyldiyl, C₂-C₂₀heterocyclyldiyl, and C₁-C₂₀ heteroaryldiyl;

Z² is selected from O, S, NR^(a), C₁-C₆ alkyldiyl, C₁-C₆fluoroalkyldiyl, O—(C₁-C₆ alkyldiyl), O—(C₁-C₆ fluoroalkyldiyl), C(O),and a bond;

R¹, R², R³ and R⁴ are independently selected from H, F, Cl, Br, I, —CN,—CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl,azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino;

R⁵ is selected from H, C₁-C₉ alkyl, C₃-C₉ cycloalkyl, C₃-C₉ heterocycle,C₆-C₉ aryl, C₆-C₉ heteroaryl, —(C₁-C₆ alkyldiyl)-(C₃-C₉ cycloalkyl),—(C₁-C₆ alkyldiyl)-(C₃-C₉ heterocycle), C(O)R^(b), C(O)NR^(a), SO₂R^(a),and SO₂NR⁸, optionally substituted with one or more of halogen, CN,OR^(a), N(R^(a))₂, C₁-C₉ alkyl, C₃-C₉ cycloalkyl, C₃-C₉ heterocycle,C₆-C₉ aryl, C₆-C₉ heteroaryl, C(O)R^(b), C(O)NR^(a), SO₂R^(a), andSO₂NR^(a);

R⁶ is selected from F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂,—CH₂NHSO₂CH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂,—CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃,—COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂,—C(CH₃)₂CONH₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃,—NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH,—OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,cyclobutyl, oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morpholinomethyl, morpholino-methanone, and morpholino; and

m is selected from 0, 1, 2, 3, and 4;

where alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocyclyldiyl,heterocyclyldiyl, and heteroaryldiyl are optionally substituted with oneor more groups independently selected from F, Cl, Br, I, —CN, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃,—N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃,—NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH,—OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H,cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl,1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino.

Formula Ia-k compounds have the structures:

wherein R⁷ is F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH,—CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)_(2J)—CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃,—CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN,—CH₂CN, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂,—NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morphdinomethyl, morpholino-methanone, and morpholino; and

n is selected from 0, 1, 2, 3, and 4;

wherein R⁸ is H or —CH₃;

Exemplary embodiments of Formula I compounds include wherein Y¹ isCR^(b) and Y³ is NR^(a).

Exemplary embodiments of Formula I compounds include wherein Y¹ is N andY³ is C(R^(b))₂.

Exemplary embodiments of Formula I compounds include wherein Y² is—(CH₂)—.

Exemplary embodiments of Formula I compounds include wherein Y² is—(CH₂CH₂)—.

Exemplary embodiments of Formula I compounds include wherein R^(c) is H.

Exemplary embodiments of Formula I compounds include wherein Cy isC₆-C₂₀ aryldiyl, C₆-C₂₀ aryldiyl is phenyldiyl, and phenyldiyl issubstituted with one or more F.

Exemplary embodiments of Formula I compounds include wherein R¹ and R²are H.

Exemplary embodiments of Formula I compounds include wherein R³ is H,and R⁴ is —CH₃.

Exemplary embodiments of Formula I compounds include wherein R⁵ is C₁-C₆fluoroalkyl.

Exemplary embodiments of Formula I compounds include wherein m is 0.

The present invention also provides tetrahydro-pyrido[3,4-b]indol-1-ylcompounds of Formula XI, including Formula XIa, and pharmaceuticalformulations thereof, which are potentially useful in the treatment ofdiseases, conditions and/or disorders modulated by Estrogen Receptoralpha (ERa).

In some embodiments, a compound of the invention has the followingstructure of Formula (XI):

wherein:

Z¹ and Z² are independently selected from —O—, —(CH₂)—, —C(O)—, or abond;

Cy is C₆-C₂₀ aryl, C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, or C₁-C₂₀heteroaryl;

X is —(CH₂)— or —(CH₂CH₂)—;

R¹ is selected from H, F, Cl, —CN, —CH₂OH, —CH(CH₃)OH, —C(CH₃)₂OH,—CH(CF₃)OH, —CH₂F, —CHF₂, —CH₂CHF₂, —CF₃, —CH₃, —C(O)NH₂, —C(O)NHCH₃,and —C(O)N(CH₃)₂;

each R² is independently selected from halogen, —CN, —OR¹⁰, —NR¹³R¹⁴,C₁-C₆ alkyl, C₃-C₈ carbocyclyl, —C₁-C₆ alkyl-OH, C₃-C₈ carbocyclyl-OH,—OC₂-C₆ alkyl-OH, C₁-C₆ fluoroalkyl, C₃-C₈ fluorocarbocyclyl,—C(═O)OR¹², —NHC(═O)R¹¹, —C(═O)NHR¹², —SO₂R¹¹, —NHSO₂R¹¹, and —SO₂NHR¹²;

R⁴ and R⁵ are each independently selected from C₁-C₆ alkyl, C₃-C₈carbocyclyl, —C₁-C₆ alkyl-OH, C₃-C₈ carbocyclyl-OH, C₁-C₆ fluoroalkyl,C₃-C₈ fluorocarbocyclyl, —C(═O)OR¹²;

R⁹ is independently selected from C₁-C₆ alkyl, C₃-C₈ carbocyclyl, —C₁-C₆alkyl-OH, C₃-C₈ carbocyclyl-OH, C₁-C₆ fluoroalkyl, C₃-C₈fluorocarbocyclyl, C₂-C₉ heterocyclyl, C₆-C₁₀ aryl, and C₁-C₁₀heteroaryl;

R¹⁹ is independently selected from H, C₁-C₆ alkyl, C₃-C₈carbocyclyl,—C₁-C₆alkyl-OH, C₃-C₈ carbocyclyl-OH, C₁-C₆ fluoroalkyl, C₃-C₈fluorocarbocyclyl, —C(═O)OR¹², —C(═O)NHR¹², —SO₂R¹¹, —NHSO₂R¹¹,—SO₂NHR¹², C₆-C₁₀ aryl, and C₁-C₁₀ heteroaryl;

each R¹⁰ is independently selected from H, C₁-C₄ alkyl, and C₁-C₄fluoroalkyl;

each R¹¹ is independently selected from C₁-C₄ alkyl and C₁-C₄fluoroalkyl;

each R¹² is independently selected from H, C₁-C₄ alkyl, and C₁-C₄fluoroalkyl;

each R¹³ and each R¹⁴ are independently selected from H and C₁-C₄ alkyl;and

m is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In some embodiments, the compound of Formula (XT) has the structure ofFormula (XIa):

wherein R^(2a) is independently H or F, n is 0, 1 or 2, and R⁴ and R⁵are independently H or methyl.

In some embodiments is a compound of Formula (XI) wherein Z¹ is a bond.In some embodiments is a compound of Formula (XI) wherein Z¹ is —O—. Insome embodiments is a compound of Formula (XI) wherein Z¹ is —(CH₂)—. Insome embodiments is a compound of Formula (XI) wherein Z¹ is —C(O)—. Insome embodiments is a compound of Formula (XI) wherein Z² is a bond. Insome embodiments is a compound of Formula (XI) wherein Z² is —O—. Insome embodiments is a compound of Formula (XI) wherein Z² is —(CH₂). Insome embodiments is a compound of Formula (XI) wherein Z² is —C(O)—. Insome embodiments is a compound of Formula (XI) wherein Cy is C₆-C₂₀aryl. In some embodiments is a compound of Formula (XI) wherein Cy isphenyl. In some embodiments is a compound of Formula (XI) wherein Cy isC₃-C₁₂ carbocyclyl. In some embodiments is a compound of Formula (XI)wherein Cy is cyclohexyl. In some embodiments is a compound of Formula(XI) wherein Cy is C₂-C₂₀ heterocyclyl. In some embodiments is acompound of Formula (XI) wherein Cy is pyrazinyl. In some embodiments isa compound of Formula (XT) wherein Cy is piperidinyl. In someembodiments is a compound of Formula (XI) wherein Cy isC₁-C₂₀heteroaryl. In some embodiments is a compound of Formula (XI)wherein Cy is thiazolyl. In some embodiments is a compound of Formula(XI) wherein Cy is oxazolyl. In some embodiments is a compound ofFormula (XI) wherein Cy is pyridyl. In some embodiments is a compound ofFormula (XI) wherein R¹ is H. In some embodiments is a compound ofFormula (XI) wherein R¹ is —CH₃. In some embodiments is a compound ofFormula (XI) wherein X is —(CH₂)—. In some embodiments is a compound ofFormula (XI) wherein X is —(CH₂)— and R¹ is H. In some embodiments is acompound of Formula (XI) wherein X is —(CH₂CH₂)—. In some embodiments isa compound of Formula (XI) wherein X is —(CH₂CH₂)— and R¹ is H. In someembodiments is a compound of Formula (XI) wherein X is —(CH₂CH₂)— and R¹is —CH₃.

In some embodiments is a compound of Formula (XI) wherein Z¹ is a bond,Z² is —O—, Cy is phenyl, X is —(CH₂)—, and R¹ is H. In some embodimentsis a compound of Formula (XI) wherein Z¹ is a bond, Z² is —O—, Cy isphenyl, X is —(CH₂CH₂)—, and R¹ is H. In some embodiments is a compoundof Formula (XI) wherein Z¹ is a bond, Z² is —O—, Cy is phenyl, X is—(CH₂CH₂)—, and R¹ is —CH₃.

BIOLOGICAL EVALUATION

The relative efficacies of Formula I compounds as inhibitors of anenzyme activity (or other biological activity) can be established bydetermining the concentrations at which each compound inhibits theactivity to a predefined extent and then comparing the results.Typically, the preferred determination is the concentration thatinhibits 50% of the activity in a biochemical assay, i.e., the 50%inhibitory concentration or “IC₅₀”. Determination of IC₅₀ values can beaccomplished using conventional techniques known in the art. In general,an IC₅₀ can be determined by measuring the activity of a given enzyme inthe presence of a range of concentrations of the inhibitor under study.The experimentally obtained values of enzyme activity then are plottedagainst the inhibitor concentrations used. The concentration of theinhibitor that shows 50% enzyme activity (as compared to the activity inthe absence of any inhibitor) is taken as the IC₅₀ value. Analogously,other inhibitory concentrations can be defined through appropriatedeterminations of activity. For example, in some settings it can bedesirable to establish a 90% inhibitory concentration, i.e., IC₉₀, etc.

Cell proliferation, cytotoxicity, and cell viability of the Formula Icompounds can be measure by the CellTiter-Glo® Luminescent CellViability Assay (Promega Corp.). The CellTiter-Glo® Luminescent CellViability Assay is a homogeneous method of determining the number ofviable cells in culture based on quantitation of the ATP present, anindicator of metabolically active cells. The CellTiter-Glo® Assay isdesigned for use with multiwell formats, making it ideal for automatedhigh-throughput screening (HTS), cell proliferation and cytotoxicityassays. The homogeneous assay procedure involves adding the singlereagent (CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium and multiplepipetting steps are not required. The system detects as few as 15cells/well in a 384-well format in 10 minutes after adding reagent andmixing.

All of the exemplary Formula I compounds in Tables 1 and 2 were made andcharacterized by LCMS [M+H]⁺ (liquid chromatography mass spectroscopy)with detection of parent ion. All of the exemplary Formula I compoundsin Tables 1 and 2 were tested for binding to ERa (Estrogen Receptoralpha) and biological activity according to the assays, protocols, andprocedures of Examples 901-907. ER-alpha MCF7 HCS S_(inf) (%) values inTable 1 were measured by the Breast Cancer Cell ERa High ContentFluorescence Imaging Degradation Assay of Example 901. ER-alpha MCF7 HCSEC₅₀ (μM) values in Tables 1 and 2 were measured by the in vitro cellproliferation assays described in Examples 902 and 903. The rat uterinewet weight assays of Examples 906 and 907 allow rapid determination ofcompound antagonist activity in an ER responsive tissue (immature ratuterus) while competing against the native ER ligand estradiol, i.e.antagonist mode (Ashby, J.; et al (1997) Regulatory toxicology andpharmacology: RTP, 25 (3):226-31). Exemplary Formula I compounds inTables 1 and 2 have the following structures, corresponding names(ChemBioDraw, Version 12.0.2, CambridgeSoft Corp., Cambridge Mass.), andbiological activity. Where more than one name is associated with aFormula I compound or intermediate, the chemical structure shall definethe compound.

TABLE 1 ER− ER-alpha alpha MCF7 MCF7 HCS EC₅₀ HCS No. Structure Name(μM) S_(inf) (%) 101

(1R,3R)-1-(2,6-difluoro-4- ((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000049 −100   102

(1R,3R)-1-(2,6-difluoro-4- (2-(3- fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000014    −98.9% 103

1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)-2-methylpropan-1-one 0.00011    −91.8% 104

1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2- methylpropan-1-one 0.000043    −95.4% 105

(1R,3R)-1-(4-(2-(3- (difluoromethyl)azetidin- 1-yl)ethoxy)-2,6-difluorophenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000027 −94% 106

(1R,3R)-1-(4-((1-(3- chloropropyl)azetidin-3- yl)oxy)-2,6-difluorophenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000142    −90.4% 107

(1R,3R)-1-(2,6-difluoro-4- ((1-propylazetidin-3- yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 0.000024    −97.6% 108

(1R,3R)-1-(2,6-difluoro-4- ((S)-2-((R)-3- (fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-2- (2-fluoro-2-methylpropyl)- 3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.00011    −79.3% 109

(1R,3R)-1-(2,6-difluoro-4- (2-((R)-3- (fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000050    −86.5% 110111

(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(6-(2-(3-(fluoromethyl)azetidin-1- yl)ethoxy)pyridin-3-yl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000898 −96.8 112

(1S,3R)-2-(2-fluoro-2- methylpropyl)-1-(3-fluoro- 5-(2-(3-(fluoromethyl)azetidin-1- yl)ethoxy)pyridin-2-yl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000092 −93.9 113

(1R,3R)-2- (cyclobutylmethyl)-1-(2,6- difluoro-4-(2-(3-(fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00618 −94.8 114

(1R,3R)-1-(2,6-difluoro-4- (2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-2-((3- methyloxetan-3- yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.000715 −97.8 115

(1R,3R)-1-(2,6-difluoro-4- (2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-2-(oxetan-3 ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.0231 −95.5 116

(1R,3R)-1-(2,6-difluoro-4- (2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-2-(oxetan-3-yl)- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 0.0414 −85   117

(1R,3R)-1-(2,6-difluoro-4- (2-(pyrrolidin-1- yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 0.000171 −71.7 118

(1R,3R)-1-(2,6-difluoro-4- (2-(piperidin-1- yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3- methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole 0.000488 −72.2 119

(1-(2-(3,5-difluoro-4- ((1R,3R)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-1- yl)phenoxy)ethyl)azetidin-3-yl)methanol 0.00198 −71.3 120

(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(2-fluoro- 4-(2-(3-(fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.0000562 −96.3 121

1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)ethanone 0.008 −91   122

1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)-2-hydroxy-2- methylpropan-1-one 0.0014 −97.8 123

(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)-2-methylpropan-1-ol 0.00104 −96.1 124

((1R,3R)-1-(2,6-difluoro- 4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)((1s,3S)-3- hydroxycyclobutyl)methan- one 0.135 −75   125

1-(1-(2,6-difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3,3- dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)- yl)-2-methylpropan-1-one 0.0744 −90   126

(1R,3R)-1-(2,6-difluoro-4- (2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-2- (methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.000469 −94.4

TABLE 2 ER-alpha MCF7 HCS EC₅₀ LCMS No. Structure Name (μM) [M + H]⁺ 127

1-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl-propan-2-ol 0.000641 502.6 128

(1R,3R)-1-[4-[2-[3- (difluoromethyl)azetidin-1- yl]ethoxy]-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000064 522.3 129

(1R,3R)-1-[4-[1-(3- chloropropyl)azetidin-3-yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.00017 522.2 130

(1R,3R)-1-[2,6-difluoro-4-(1- propylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.0000504 486.3 131

((1S,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2- fluoro-2-methylpropyl)- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3- yl)methanol 0.000146 520.3 132

(1R,3R)-1-[4-(azetidin-3- yloxy)-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)- 3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.00031 444.2 133

(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(2-fluoro-4-(2-(3-(fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.0000562 486.3 134

(1R,3R)-2-cyclobutyl-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indole0.000542 484.3 135

(1R,3S)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- (fluoromethyl)-2-(2-fluoro-2-methyl-propyl)-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.0000973 522.3136

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-[(3- fluorooxetan-3-yl)methyl]-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000114 518.3 137

cyclohexyl((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)methanone 0.028 540.4 138

1-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2,2-dimethyl-propan-1- one 0.000491 514.3 139

cyclopropyl((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)methanone 0.00248 498.2 140

(1R,3R)-1-[2,6-difluoro-4-[2- (3-methylazetidin-1-yl)ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.00013 486.4 141

(1R,3R)-1-(2,6-difluoro-4-(2- ((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000151 500.2 142

(1R,3R)-1-[2,6-difluoro-4- [(2S)-2-pyrrolidin-1- ylpropoxy]phenyl]-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole0.000090 500.3 143

(1R,3R)-1-[2,6-difluoro-4-[3- [3-(fluoromethyl)azetidin-1-yl)propoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000078 518.4 144

(1R,3R)-1-[2,6-difluoro-4- [(E)-3-[3- (fluoromethyl)azetidin-1-yl]prop-1-enyl]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000144 500.1 145

N-(3,5-difluoro-4-((1R,3R)-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1- yl)phenyl)-1-(3-fluoropropyl)azetidin-3- amine 0.000096 503.3 146

(1R,3R)-2-[(3,3- difluorocyclobutyl)methyl]-1- [2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.01 534.3 147

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2,2- dimethylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000698 500.3 148

cyclobutyl-[(1R,3R)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]methanone 0.00147 512.3 149

cyclopentyl-(1R,3R)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]methanone 0.00216 526.4 150

(1R,3R)-1-[2,6-difluoro-4-[2- [(3S)-3-methylpyrrolidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000483 500.2 151

(1R,3R)-1-[2,6-difluoro-4- [(2R)-2-pyrrolidin-1- ylpropoxy]phenyl]-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole0.000156 500.1 152

(1R,3R)-1-[2,6-difluoro-4- [(1-propylazetidin-3- yl)methoxy]pheny]-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole0.000362 500.3 153

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-[(1- fluorocyclobutyl)methyl]-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000221 516.3 154

(S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2- methylpropan-1-ol 0.0000333 520.3 155

(2R)-3-[(1R,3R)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2- methyl-propan-1-ol 0.0000799 520.3 156

(1R,3R)-1-[4-[2-[3- (fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole0.000335 468.3 157

2-cyclopropyl-1-[(1R,3R)-1- [2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]ethanone 0.005 512.4 158

2-cyclobutyl-1-[(1R,3R)-1- [2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]ethanone 0.01 526.4 159

1-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1- one 0.000147 522.3 160

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)-3-methyl-azetidin-1-yl]ethoxy]phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000285 518.4 161

(1R,3R)-1-[2,6-difluoro-4-(1- methylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.0000413 458.3 162

(1R,3R)-1-[4-(1- ethylazetidin-3-yl)oxy-2,6-difluoro-phenyl]-2-(2-fluoro- 2-methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.0000528 472.2 163

(1R,3R)-1-[2,6-difluoro-4-(1- pentylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000457 513.9 164

(1R,3R)-1-[4-[1- (cyclopropylmethyl)azetidin- 3-yl]oxy-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000216 498.4 165

(1R,3R)-1-[4-[1- (cyclopentylmethyl)azetidin- 3-yl]oxy-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.002 526.5 166

(1R,3R)-1-[2,6-difluoro-4-[1- (2-fluoroethyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrabydropyrido[3,4- b]indole 0.000175 490.4 167

(1R,3R)-1-[2,6-difluoro-4-(1- prop-2-ynylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000083 482.3 168

(1R,3R)-1-[2,6-difluoro-4-(1- isopropylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000122 486.4 169

(1R,3R)-1-[2,6-difluoro-4-(1- isobutylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000409 400.3 170

tert-butyl 3-[3,5-difluoro-4- [(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]phenoxy]azetidine-1- carboxylate 0.001 544.3 171

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-ethyl-2- (2-fluoro-2-methylpropyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.000471 518.3 172

(1R,3S)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-ethyl-2- (2-fluoro-2-methylpropyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.017 518.3 173

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-[(1- methylcyclobutyl)methyl]-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.001 512.3 174

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000285 512.2 175

(1S,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.014 512.2 176

(1R,3R)-1-[4-[1-(3,3- dimethoxypropyl)azetidin-3-yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000031 546.3 177

(1R,3R)-1-[2-fluoro-4-[1-(3- fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000164 486.3 178

1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.0005 490.2 179

(1S,3R)-1-[4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.013 472.2 180

(1R,3R)-1-(4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.000222 472.2 181

1-((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 3-hydroxy-2-methylpropan-1- one 0.004516.2 182

azetidin-3-yl-[(1R,3R)-1-[2,6- difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]methanone >0.1 513.3 183

((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H- pyrido[3,4-b]indol-2(9H)-yl)(2- fluorocyclopropyl)methanone 0.004 516.3 184

(1R,3R)-1-[2,6-difluoro-4- [(2S)-2-[(3R)-3- methylpyrrolidin-1-yl]propoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000494 514.4 185

[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-phenyl-methanone 0.014 534.2 186

(1R,3R)-2- (cyclopropylmethyl)-1-[2,6- difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.002 484.4 187

(1R,3R)-1-[4-[1-(2- cyclopropylethyl)azetidin-3-yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.001 512.4 188

(1R,3R)-1-[4-(1-allylazetidin- 3-yl)oxy-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000128 484.3 189

(1R,3R)-1-[4-[1- (cyclobutylmethyl)azetidin-3-yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.001 512.3 190

(1R,3R)-1-[2,6-difluoro-4-(1- isopentylazetidin-3-yl)oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.002 514.3 191

(1R,3R)-1-(2,6-difluoro-4- ((1-(2-methylbutyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro- 2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.000267 514.3 192

(1R,3R)-1-(2,6-difluoro-4- ((1-(pentan-2-yl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.001 514.3 193

(1R,3R)-1-[4-(1- cyclobutylazetidin-3-yl)oxy- 2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole0.000484 498.3 194

(1R,3R)-1-[2,6-difluoro-4-[1- (oxetan-3-yl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000077 500.2 195

(1R,3R)-1-[4-(1- cyclopropylazetidin-3-yl)oxy-2,6-difluoro-phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000165 484.3 196

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]sulfanyl-phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000271 520.3 197

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-isobutyl- 3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.001 486.2 198

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 2-((R)-2-phenylpropyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.002 548.1 199

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 2-((S)-2-phenylpropyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.00232 548.3 200

(1R,3R)-1-[2,6-difluoro-4-(1- propylazetidin-3-yl)oxy-phenyl]-2-isobutyl-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indole0.000408 468.3 201

(1R,3R)-2-(2-fluoro-2- methyl-propyl)-1-[4-[1-(3-fluoropropyl)azetidin-3- yl]oxyphenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000315 202

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl-2- methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.0001 508.2 203

[1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-(3- fluorocyclobutyl)methanone 0.004 530.4 204

(1R,3R)-1-[4-[(2S)-2-[3- (difluoromethyl)azetidin-1-yl]propoxy]-2,6-difluoro- phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000371 536.4205

(1R,3R)-1-[2,6-difluoro-4-[2- [3-fluoro-3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000375 522.1 206

4-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-4-oxo-butanenitrile 0.031 511.3 207

(1R,3R)-2- (cyclohexylmethyl)-1-[2,6- difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.013 526.4 208

(1R,3R)-1-[2,6-difluoro-4-[1- [2-(oxetan-3- yl)ethyl]azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000066 528.3 209

(1R,3R)-1-[4-[1- (cyclohexylmethyl)azetidin- 3-yl]oxy-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.008 540.3 210

(1R,3R)-1-[2-chloro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.0001 503.2 211

(1R,3R)-1-[2-chloro-4-[1-(3- fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.0002 503.2 212

1-((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 3-hydroxybutan-1-one 0.001 538.2 213

[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-(oxetan-3-yl)methanone 0.004 514.2 214

[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-(thietan-3-yl)methanone 0.004 530.2 215

(R)-1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3- fluoro-2-methylpropan-1-one 0.000335 518.3216

(1R,3R)-2- (cyclopentylmethyl)-1-[2,6- difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.001 512.4 217

(1R,3R)-1-[4-[1-[(4,4- difluorocyclohexyl)methyl]azetidin-3-yl]oxy-2,6-difluoro- phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.002 576.3 218

(S)-1-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-3- fluoro-2-methylpropan-1-one 0.000402 518.3219

((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2- yl)(oxetan-2-yl)methanone 0.035 514.2 220

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole0.007 430.2 221

2-fluoro-1-[(1R,3R)-1-[4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propan-1-one 0.18 482.3 222

1-[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2- methyl-propan-1-one 0.0004 518.2 223

1-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2- (dimethylamino)ethanone 0.038 515.2 224

(1R,3R)-1-[2,6-difluoro-4-[1- [(1- fluorocyclopropyl)methyl]azetidin-3-yl]oxy-phenyl]-2-(2- fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000316 516.2 225

[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]-(1-fluorocyclobutyl)methanone 0.001 530.1 226

[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]-(1-methylcyclopropyl)methanone 0.002 512.1 227

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-[[1- (fluoromethyl)cyclopropyl]methyl]-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.00017 516.1228

[1-[[(1R,3R)-1-[2,6-difluoro- 4-[1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]methyl]cyclopropyl]methanol 0.001 514.2 229

2-fluoro-1-[(1S,3R)-1-[2- fluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propan-1-one 0.025 500.2 230

2-fluoro-1-[(1R,3R)-1-[2- fluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propan-1-one 0.000068 500.2 231

(1S,3R)-1-[2-fluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.024 490.2 232

(1R,3R)-1-[2-fluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000192 490.2 233

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- fluoro-2-methylpropan-1-ol 0.000133 520.3234

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- fluoro-2-methylpropan-1-ol 0.00018 520.3 235

2-fluoro-1-((1S,3R)-1-[4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propan-1-one 0.024 482.3 236

(1R)-1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000182 490.2 237

(1S)-1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.046 490.2 238

[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4- b]indol-2-yl]-(1-fluorocyclopropyl)methanone 0.000244 516.1 239

(1R,3R)-6-chloro-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.00156 538.1 240

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-7-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000261 522.2 241

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000381 522.3 242

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00542 522.3 243

(1-(((1R,3R)-1-(2,6-difluoro- 4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)methyl)cyclopropyl)methanol 0.002 514.2 244

(1S,3S)-6-chloro-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.063 538.1 245

(1S,3S)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.035 522.3 246

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl-2- [(3-methyloxetan-3- yl)methyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000358 536.1 247

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-5-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00434 522.2 248

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-7-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000518 522.2 249

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-5-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000511 522.2 250

(1R,3R)-2-(2-fluoro-2- methyl-propyl)-1-[4-[2-[(3R)-3-(fluoromethyl)pyrrolidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000275 482.2 251

(1S,3S)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-5-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.021 522.2 252

(1S,3S)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-7-fluoro-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.05 522.3 253

(1S,3S)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-5-fluoro-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.035 522.2 254

2-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-N,N-dimethyl- acetamide 0.04 515.2 255

3-((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.000010 520.2256

(1R,3R)-2-(2-fluoro-2- methyl-propyl)-1-[4-[1-(3-fluoropropyl)azetidin-3- yl]oxy-2-methyl-phenyl]-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.00169 257

(1R)-1-[2,6-difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-2-(2- fluoro-2-methyl-propyl)-3,3-dimethyl-4,9-dihydro-1H- pyrido[3,4-b]indole 0.00109 518.3 258

(S)-1-(2,6-difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.031 518.3 259

(1R,3R)-1-[4-[1-[(3,3- difluorocyclobutyl)methyl]azetidin-3-yl]oxy-2,6-difluoro- phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000444 538.3260

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-8-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000881 522.3 261

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-8-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00028 522.3 262

(1S,3S)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-8-fluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.026 522.3 263

(S)-1-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)propan-2-ol 0.000359 488.3 264

(R)-1-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)propan-2-ol 0.000969 488.3 265

(1R,3R)-1-[4-[2-[3- (chloromethyl)azetidin-1- yl]ethoxy]-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl- propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.0017 521.2 266

(1R,3R)-1-[3-chloro-4-[1-(3- fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.01 503.2 267

(1R,3R)-1-[3-fluoro-4-[1-(3- fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000744 486.3 268

(2R)-3-[(1R,3R)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]propane-1,2-diol 0.008 504.2 269

(1R,3R)-1-[2,6-difluoro-4-[1- [[(1S,2R)-2- fluorocyclopropyl]methyl]azetidin-3-yl]oxy-phenyl]-2-(2- fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.001 516.3 270

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-((S)-3- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000459 504.3 271

(S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3 (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropane-1,2-diol 0.005 518.3 272

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(3-fluoro- 2,2-dimethyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000685 518.3 273

(R)-2-fluoro-3-((1R,3R)-1-(2- fluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropan-1-ol 0.00028 502.2 274

(S)-2-fluoro-3-((1R,3R)-1-(2- fluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropan-1-ol 0.000253 524.1 275

(R)-2-fluoro-3-((1R,3R)-1-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-methylpropan-1-ol 0.000166 484.2 276

(S)-2-fluoro-3-((1R,3R)-1-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-methylpropan-1-ol 0.000309 484.2 277

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl-2- (2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.000090 512.2 278

(2R)-3-[(1R,3R)-1-[2,6- difluoro-4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propane-1,2-diol 0.00031 518.3 279

(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(3-fluoro-4-(2-(3-(fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00016 486.3 280

(1S,3R)-2-(2-fluoro-2- methylpropyl)-1-(3-fluoro-4-(2-(3-(fluoromethyl)azetidin- 1-yl)ethoxy)phenyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.006 486.3 281

(1R,3R)-1-(2,3-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000183 504.3 282

(1R,3R)-1-(2,6-difluoro-4- ((1-(((1S,2S)-2- fluorocyclopropyl)methyl)azetidin-3-yl)oxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.001 516.3 283

1-[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]propan-2-one 0.001 486.3 284

3-[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-dimethyl- propan-1-ol 0.000382 516.3 285

(1R,3R)-1-[2,6-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-2- ethylsulfonyl-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indole 0.002 522.1 286

3-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol 0.0000978 524.1 287

3-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2,2-dimethyl-propan-1- ol 0.001 516.3 288

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- fluoro-2-methylpropan-1-ol 0.0000528 519.3289

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- fluoro-2-methylpropan-1-ol 0.000199 519.3290

(R)-2-fluoro-3-((1R,3R)-1-(2- fluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropan-1-ol 0.000497 501.3 291

(S)-2-fluoro-3-((1R,3R)-1-(2- fluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropan-1-ol 0.00013 501.3 292

(R)-2-fluoro-3-((1R,3R)-1-(4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropan-1-ol 0.002 483.3 293

(S)-2-fluoro-3-((1R,3R)-1-(4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropan-1-ol 0.00015 483.3 294

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- fluoro-2-methylpropan-1-ol 520.3 295

1-((1S,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)propan-2-one 0.021 486.2 296

3,5-difluoro-N-(2-(3- (fluoromethyl)azetidin-1- yl)ethyl)-4-((1R,3R)-3-methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)aniline 0.0002 511.2 297

(S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- N,N,2-trimethylpropanamide 0.018 543.3 298

(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- N,N,2-trimethylpropanamide 0.005 543.3 299

(S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropanoic acid 0.003 516.2 300

(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropanoic acid 0.001 516.2 301

(1R,3S)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3- (fluoromethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.0000881 522.2 302

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2- difluoropropan-1-ol 0.00012 524.1 303

(1R,3R)-2-(2,2- difluoroethyl)-1-[2,6- difluoro-4-[1-(3-fluoropropyl)azetidin-3- yl]oxy-phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.0000482 494.2 304

N-(3,5-difluoro-4-((1R,3R)-3- methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3- amine 0.000224 511.2 305

(1R,3R)-2-(2,2- difluoroethyl)-1-[2,6- difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000216 494.2 306

(1S,3R)-2-(2,2-difluoroethyl)- 1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.003 494.2 307

(1R,3R)-1-[4-[1-(3,3- difluorocyclobutyl)azetidin-3-yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000193 534.1 308

(1R,3R)-1-[2,6-difluoro-4-[1- [(E)-3-fluoroallyl]azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000127 502.3 309

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl-2- (2-(methylsulfonyl)propyl)-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.006 550.3 310

1-(3-fluoropropyl)-N-[4- [(1R,3R)-3-methyl-2- methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indol- 1-yl]phenyl]azetidin-3-amine 0.000708471.2 311

N-[3,5-difluoro-4-[(1R,3R)-3- methyl-2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]phenyl]-1-(3-fluoropropyl)azetidin-3- amine 0.000248 507.2 312

(1R,3R)-1-[4-[2-[3- (fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-vinylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole 0.002 484.1 313

(1R,3R)-1-[4-[2-[3- (fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-N,3-dimethyl-1,3,4,9- tetrahydropyrido[3,4- b]indole-2-sulfonamide 0.001487.4 314

1-(3-fluoropropyl)-N-[4- [(1S,3R)-3-methyl-2- methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indol- 1-yl]phenyl]azetidin-3-amine 0.009 471.3315

N-[3,5-difluoro-4-[(1S,3R)-3- methyl-2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]phenyl]-1-(3-fluoropropyl)azetidin-3- amine 0.002 507.1 316

3-[(1R,3R)-1-[2,6-difluoro-4- [1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-dimethyl- propanenitrile 0.0000724 511.2 317

(1R,3R)-1-[4-[1-(3,3- difluoroallyl)azetidin-3-yl]oxy-2,6-difluoro-phenyl]- 2-(2-fluoro-2-methyl-propyl)-3-methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.000181 520.1 318

(S)-2-(((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)methyl)-3,3,3- trifluoropropan-1-ol 0.001 556.2 319

(R)-2-(((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)methyl)-3,3,3- trifluoropropan-1-ol 0.00043 556.2 320

3-((1R,3R)-1-(2,6-difluoro-4- ((2-(3-(fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.00027 519.2321

3,5-difluoro-N-[2-[3- (fluoromethyl)azetidin-1-yl]ethyl]-4-[(1R,3R)-2-(2- fluoro-2-methyl-propyl)-3- methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol- 1-yl]aniline 0.000222 503.2 322

3-fluoro-N-[2-[3- (fluoromethyl)azetidin-1- yl]ethyl]-4-[(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-1-yl]aniline 0.0000253 485.2 323

N-[2-[3- (fluoromethyl)azetidin-1- yl]ethyl]-4-[(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-1-yl]aniline 0.000215 467.2 324

(1R,3R)-2-ethylsulfonyl-1-[4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indole0.000198 486.2 325

N-[2-[3- (fluoromethyl)azetidin-1- yl]ethyl]-4-[(1R,3R)-3-methyl-2-methylsulfonyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]aniline 0.001 471.1 326

3,5-difluoro-N-[2-[3- (fluoromethyl)azetidin-1- yl]ethyl]-4-[(1R,3R)-3-methyl-2-methylsulfonyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]aniline 0.000305 507.2 327

2-fluoro-3-((1R,3R)-1-(2- fluoro-4-((2-(3- (fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-methylpropan-1-ol 0.000347 501.2 328

2-fluoro-3-((1R,3R)-1-(4-((2- (3-(fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-methylpropan-1-ol 0.000167 483.3 329

(1R,3R)-1-[4-[2-[3- (fluoromethyl)azetidin-1- yl]ethoxy]phenyl]-N,N,3-trimethyl-1,3,4,9- tetrahydropyrido[3,4- b]indole-2-sulfonamide 0.001523.1 330

(1R,3R)-1-[4-[1-(3- fluoropropyl)azetidin-3- yl]oxyphenyl]-3-methyl-2-methylsulfonyl-1,3,4,9- tetrahydropyrido[3,4-b]indole 0.002 472.2 331

3-[3-[3,5-difluoro-4- [(1R,3R)-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1- yl]phenoxy]azetidin-1-yl]cyclobutanol 0.000236 514.2 332

(1R,3R)-1-(4-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-2-((S)-isopropylsulfinyl)-3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole0.008 484.2 333

(1R,3R)-1-(4-(2-(3- (fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-2-((R)-isopropylsulfinyl)-3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole0.048 484.2 334

(1S,3s)-3-(3-(3,5-difluoro-4- ((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl- 2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-1-yl)phenoxy)azetidin-1- yl)cyclobutanol 0.00013 514.2 335

(1R,3R)-1-[2,6-difluoro-4-[1- (5-fluoropentyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000442 532.3 336

(1R,3R)-1-[3,5-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000263 504.3 337

(1R,3R)-1-[2,6-difluoro-4-[1- (4-fluorobutyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.000387 518.3 338

(1R,3R)-1-[3,5-difluoro-4-[1- (5-fluoropentyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.001 532.2 339

(1R,3R)-1-[2,5-difluoro-4-[1- (3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.001 504.2 340

3-[(1R,3R)-1-[2,6-difluoro-4- [[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro- propan-1-ol 0.000203 523.2 341

3-[(1R,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethylamino]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol 0.000348 545.2 342

(1S,3R)-2-(2-fluoro-2- methylpropyl)-1-(5-((1-(3-fluoropropyl)azetidin-3- yl)oxy)pyrazin-2-yl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000619 470.3 343

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)-3- methylazetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.0002 518.3 344

2-[(1R,3R)-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]-5-[1-(3-fluoropropyl)azetidin-3- yl]oxy-benzonitrile 0.000347 493.3 345

4-((1R,3R)-2-(2-fluoro-2- methylpropyl)-3-methyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-1-(3- (3-(fluoromethyl)azetidin-1-yl)propyl)pyridin-2(1H)-one 0.0123 483.3 346

[4-[(1R,3R)-2-(2-fluoro-2- methyl-propyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]phenyl]-[1-(3-fluoropropyl)azetidin-3- yl]methanone 0.000399 480.2 347

(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropanamide 0.014 515.3 348

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropanoic acid 0.001 516.2 349

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2- methylpropanoic acid 0.00203 515.2 350

3-[1-[2,6-difluoro-4-[1-(3- fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propanoic acid 0.014 516.2 351

3-[1-[2,6-difluoro-4-[1-(3- fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propanoic acid 0.033 516.2 352

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((2-(3- (fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.000685 519.3353

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((2-(3- (fluoromethyl)azetidin-1-yl)ethyl)amino)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.000033 519.3354

(2R)-3-[(1R,3R)-1-[2,6- difluoro-4-[[1-(3- fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propanoic acid 0.001 514.2 355

(1S,3S)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-fluoro-3- methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.0292 530.2 356

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-fluoro-3- methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.000509 530.2 357

(1S,3S)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.0261 529.5 358

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-2-(2,2,2- trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indole 0.000417 529.5 359

3-((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-difluoropropan-1-ol 0.000552 541.5 360

3-((1S,3S)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-difluoropropan-1-ol 0.009 541.5 361

(1R,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole 0.003 525.5 362

(1S,3R)-1-[2,6-difluoro-4-[2- [3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl- 2-(3,3,3-trifluoropropyl)-1,3,4,9-tetrahydropyrido[3,4- b]indole >0.1 526.2 363

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-difluoropropan-1-ol 0.000166 542.1 364

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-difluoropropan-1-ol 0.009 542.1 365

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-difluoropropan-1-ol 0.000233 541.2 366

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro- 3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-difluoropropan-1-ol 0.004 541.2 367

(2S)-3-[(1R,3R)-1-[2,6- difluoro-4-[[1-(3- fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl- 1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl- propanoic acid 0.008 515.3 368

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.000546 538.3369

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.024 538.3370

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.000203 538.3371

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.009 538.3372

N-(3,5-difluoro-4-((1R,3R)-6- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.000198 529.2373

N-(3,5-difluoro-4-((1S,3S)-6- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.018 529.2374

3-((1R,3R)-1-(2,6-difluoro-4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2,2-dimethylpropanoic acid 0.00155 530.3375

(R)-2-(((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)methyl)-3,3,3- trifluoropropan-1-ol 0.000764 556.2 376

(S)-2-(((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)oxy)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)methyl)-3,3,3- trifluoropropan-1-ol 0.001 556.2 377

(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(2-((1-(3-fluoropropyl)azetidin-3- yl)oxy)pyrimidin-5-yl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.0005 470.3 378

3-[(1S,3R)-1-[2,6-difluoro-4- [2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3- methyl-1,3,4,9- tetrahydropyrido[3,4-b]indol-2-yl]-2,2-dimethyl-propanoic acid 0.028 530.3 379

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.00028 508.2 380

(S)-(4-((1R,3R)-2-(2-fluoro- 2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-1- yl)phenyl)(1-(3-fluoropropyl)azetidin-3- yl)methanol 0.000188 482.3 381

(R)-(4-((1R,3R)-2-(2-fluoro- 2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indol-1- yl)phenyl)(1-(3-fluoropropyl)azetidin-3- yl)methanol 0.000605 482.3 382

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2- dimethylpropanoic acid 0.00101 528.2 383

(1R,3R)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2,2- difluoroethyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00028 512.2 384

(1S,3S)-1-(2,6-difluoro-4-(2- (3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2,2- difluoroethyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.029 512.2 385

(1R,3R)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoroethyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000074 512.2 386

(1S,3S)-1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoroethyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.023 512.2 387

N-(3,5-difluoro-4-((1R,3R)-6- fluoro-3-methyl-2- (methylsulfonyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4- b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3- amine 0.000149 525.2 388

N-(3,5-difluoro-4-((1S,3S)-6- fluoro-3-methyl-2-(methylsulfonyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.019 525.2389

N-(4-((1R,3R)-2-(2,2- difluoroethyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.000056 511.2390

N-(4-((1S,3S)-2-(2,2- difluoroethyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.0097 511.2391

(1R,3R)-1-(2,6-difluoro-4-((1- cis-(3- (fluoromethyl)cyclobutyl)azetidin-3-yl)oxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00015 530.3 392

(1R,3R)-1-(2,6-difluoro-4-((1- trans-(3- (fluoromethyl)cyclobutyl)azetidin-3-yl)oxy)phenyl)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00044 530.3 393

(1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-((1- fluorocyclobutyl)methyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.000142 516.3 394

(S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2- fluoropropan-1-ol 0.00023 506.2 395

(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2- fluoropropan-1-ol 0.000053 506.2 396

N-(3,5-difluoro-4-((1R,3R)-7- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.00011 529.2397

N-(3,5-difluoro-4-((1S,3S)-7- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.033 529.2398

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-5-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.00011 537.3399

(R)-3-((1S,3S)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-5-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.0011 537.3400

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-5-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.000023537.3 401

(S)-3-((1S,3S)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-5-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.0024 537.3402

(R)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2- (fluoromethyl)propan-1-ol 0.000032 520.3 403

(S)-3-((1R,3R)-1-(2,6- difluoro-4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2- (fluoromethyl)propan-1-ol 0.00013 520.3 404

N-(3,5-difluoro-4-((1R,3R)-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indol-1- yl)phenyl)-1-(3-fluoropropyl)-N- methylazetidin-3-amine 0.000745 517.3 405

(R)-N-(4-(2-(2,2- difluoroethyl)-3,3-dimethyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5- difluorophenyl)-1-(3-fluoropropyl)azetidin-3- amine 0.00023 517.3 406

(S)-N-(4-(2-(2,2- difluoroethyl)-3,3-dimethyl- 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5- difluorophenyl)-1-(3-fluoropropyl)azetidin-3- amine 0.0018 507.3 407

N-(3,5-difluoro-4-((1R,3R)-5- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.00012 529.2408

N-(3,5-difluoro-4-((1S,3S)-5- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phcnyl)-1-(3- fluoropropyl)azetidin-3- amine 0.0063 529.2409

N-(3,5-difluoro-4-((1S,3S)-8- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.026 529.2410

N-(3,5-difluoro-4-((1R,3R)-8- fluoro-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9- tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3- fluoropropyl)azetidin-3- amine 0.00012 529.2411

(1R,3R)-1-(2,6-difluoro-4-(1- (3-fluoropropyl)azetidin-3-yloxy)phenyl)-2-((3- fluorooxetan-3-yl)methyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00007 518.3 412

(S)-3-((1S,3S)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-7-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.0013 537.3413

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-7-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.000018537.3 414

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-7-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.00012 537.3415

(R)-3-((1S,3S)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-7-fluoro-3- methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2-fluoro-2-methylpropan-1-ol 0.0095 537.3416

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-5-fluoro- 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.000024 541.2 417

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-5-fluoro- 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.0033 541.2 418

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2- (hydroxymethyl)propanenitrile 0.000033530.3 419

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl- 3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2- (hydroxymethyl)propanenitrile 0.000026530.3 420

(R)-3-(1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3,3- dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.000117 537.3 421

(S)-3-(1-(2,6-difluoro-4-((1- (3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3,3- dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.000146 537.3 422

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-8-fluoro- 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.0371 541.2 423

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-8-fluoro- 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.000089 541.2 424

(1R,3R)-1-(2,6-difluoro-4-(1- (3-fluoropropyl)azetidin-3-yloxy)phenyl)-6,8-difluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.0005 540.3 425

3-((1R,3R)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-7-fluoro- 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.000021 541.3 426

3-((1S,3S)-1-(2,6-difluoro-4- ((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-7-fluoro- 3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)- 2,2-difluoropropan-1-ol 0.00638 541.2 427

(1R,3R)-1-(2,6-difluoro-4-((1- ((1- (fluoromethyl)cyclopropyl)methyl)azetidin-3- yl)oxy)phenyl)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido[3,4-b]indole 0.000278 530.3 428

(1R,3R)-1-(2,6-difluoro-4-(1- (3-fluoropropyl)azetidin-3-yloxy)phenyl)-6,7-difluoro-2- (2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.0007 540.3 429

(1R,3R)-2-(2-fluoro-2- methylpropyl)-1-(1-((1-(3-fluoropropyl)azetidin-3- yl)methyl)-1H-pyrazol-4-yl)-3-methyl-2,3,4,9-tetrahydro- 1H-pyrido[3,4-b]indole 0.00099 456.3 430

N-[4-[(1R,3R)-2-(2,2- difluoroethyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4- b]indol-1-yl]-3,5-difluoro- phenyl]-1-(3-fluoropropyl)azetidin-3- amine 0.000065 493.2 431

(R)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.0000943537.3 432

(S)-3-((1S,3S)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.00327 537.3433

(S)-3-((1R,3R)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.0000209537.3 434

(R)-3-((1R,3S)-1-(2,6- difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3- methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)- 2-fluoro-2-methylpropan-1-ol 0.000706 537.3

Administration of Formula I Compounds

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound is administered orally,it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound isadministered parenterally, it may be formulated with a pharmaceuticallyacceptable parenteral vehicle and in a unit dosage injectable form, asdetailed below.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula I compound. A typical dose may be about 100 mg to about300 mg of the compound. A dose may be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula I Compounds

Formula I compounds of the present invention are useful for treating ahuman or animal patient suffering from a disease or disorder arisingfrom abnormal cell growth, function or behavior associated with USP7such as an immune disorder, cardiovascular disease, viral infection,inflammation, a metabolism/endocrine disorder or a neurologicaldisorder, may thus be treated by a method comprising the administrationthereto of a compound of the present invention as defined above. A humanor animal patient suffering from cancer may also be treated by a methodcomprising the administration thereto of a compound of the presentinvention as defined above. The condition of the patient may thereby beimproved or ameliorated.

Methods of the invention also include treating cancer selected frombreast, ovary, cervix, prostate, testis, genitourinary tract, esophagus,larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma,lung, epidermoid carcinoma, large cell carcinoma, non-small cell lungcarcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccalcavity, naso-pharyngeal, pharynx, lip, tongue, mouth, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's, leukemia, bronchus, thyroid, liver and intrahepatic bileduct, hepatocellular, gastric, glioma/glioblastoma, endometrial,melanoma, kidney and renal pelvis, urinary bladder, uterine corpus,uterine cervix, multiple myeloma, acute myelogenous leukemia, chronicmyelogenous leukemia, lymphocytic leukemia, chronic lymphoid leukemia(CLL), myeloid leukemia, oral cavity and pharynx, non-Hodgkin lymphoma,melanoma, and villous colon adenoma.

PHARMACEUTICAL FORMULATIONS

In order to use a compound of this invention for the therapeutictreatment of mammals including humans, it is normally formulated inaccordance with standard pharmaceutical practice as a pharmaceuticalcomposition. According to this aspect of the invention there is provideda pharmaceutical composition comprising a compound of this invention inassociation with a pharmaceutically acceptable diluent or carrier.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. Suitable carriers,diluents and excipients are well known to those skilled in the art andinclude materials such as carbohydrates, waxes, water soluble and/orswellable polymers, hydrophilic or hydrophobic materials, gelatin, oils,solvents, water and the like. The particular carrier, diluent orexcipient used will depend upon the means and purpose for which thecompound of the present invention is being applied. Solvents aregenerally selected based on solvents recognized by persons skilled inthe art as safe (GRAS) to be administered to a mammal. In general, safesolvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the compound (e.g.,complex with a cyclodextrin derivative or other known complexationagent) is dissolved in a suitable solvent in the presence of one or moreof the excipients described above. The compound of the present inventionis typically formulated into pharmaceutical dosage forms to provide aneasily controllable dosage of the drug and to enable patient compliancewith the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula I having the desired degree of purity mayoptionally be mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16th edition, Osol, A. Ed.), in the form of a lyophilized formulation,milled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers, i.e.,carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but may range fromabout 3 to about 8. Formulation in an acetate buffer at pH 5 is asuitable embodiment.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention will be formulated,dosed and administered in a fashion, i.e., amounts, concentrations,schedules, course, vehicles and route of administration, consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The “therapeutically effective amount”of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to ameliorate, ortreat the hyperproliferative disorder.

As a general proposition, the initial pharmaceutically effective amountof the inhibitor administered parenterally per dose will be in the rangeof about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-eresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as GDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations of compounds of Formula I may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of a compound of FormulaI. Compressed tablets may be prepared by compressing in a suitablemachine the active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl di stearate alone or with a wax may beemployed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.07S to 20% w/w. When formulated in an ointment, the active ingredientsmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients may be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base may include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs. The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it desirably comprises a mixture ofat least one emulsifier with a fat or an oil or with both a fat and anoil. Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizers) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween®60, Span® 80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, glyceryl mono-stearate and sodium laurylsulfate.

Aqueous suspensions of Formula I compounds contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withadditional therapeutic agents for the treatment of a disease or disorderdescribed herein, such as inflammation or a hyperproliferative disorder(e.g., cancer). In certain embodiments, a compound of Formula I iscombined in a pharmaceutical combination formulation, or dosing regimenas combination therapy, with an additional, second therapeutic compoundthat has anti-inflammatory or anti-hyperproliferative properties or thatis useful for treating an inflammation, immune-response disorder, orhyperproliferative disorder (e.g., cancer). The additional therapeuticmay be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTORinhibitor, an anti-inflammatory agent, an immunomodulatory agent,chemotherapeutic agent, an apoptosis-enhancer, a neurotropic factor, anagent for treating cardiovascular disease, an agent for treating liverdisease, an anti-viral agent, an agent for treating blood disorders, anagent for treating diabetes, and an agent for treating immunodeficiencydisorders. The second therapeutic agent may be an NSAIDanti-inflammatory agent. The second therapeutic agent may be achemotherapeutic agent. The second compound of the pharmaceuticalcombination formulation or dosing regimen preferably has complementaryactivities to the compound of Formula I such that they do not adverselyaffect each other. Such compounds are suitably present in combination inamounts that are effective for the purpose intended. In one embodiment,a composition of this invention comprises a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, in combination with a therapeuticagent such as an NSAID.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other therapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of therapy, a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, may be combined with othertherapeutic, hormonal or antibody agents such as those described herein,as well as combined with surgical therapy and radiotherapy. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of Formula I, or a stereoisomer,tautomer, solvate, metabolite, or pharmaceutically acceptable salt orprodrug thereof, and the use of at least one other cancer treatmentmethod. The amounts of the compound(s) of Formula I and the otherpharmaceutically active therapeutic agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is used in combination with an aromataseinhibitor, a phosphoinositide 3-kinase (PI3K)/mTOR pathway inhibitor, aCDK 4/6 inhibitor, a HER-2 inhibitor, an EGFR inhibitor, a PD-1inhibitor, poly ADP-ribose polymerase (PARP) inhibitor, a histonedeacetylase (HDAC) inhibitor, an HSP90 inhibitor, a VEGFR inhibitor, anAKT inhibitor, chemotherapy, or any combination thereof.

In some embodiments, a pharmaceutical composition comprising a compoundof Formula I, or a pharmaceutically acceptable salt thereof, isadministered in combination with a therapeutic agent selected frompaclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin,fulvestrant, letrozole, gemcitabine, trastuzumab (HERCEPTIN®,Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim,filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine,and ixabepilone.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is used in combination with hormone blockingtherapy, chemotherapy, radiation therapy, monoclonal antibodies, orcombinations thereof.

Hormone blocking therapy includes the use of agents that block theproduction of estrogens or block the estrogen receptors. In someembodiments, hormone blocking therapy includes the use of estrogenreceptor modulators and/aromatase inhibitors. Estrogen receptormodulators include triphenylethylene derivatives (e.g. tamoxifen,toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (aphosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (acarboxylic acid derivative of tamoxifen)); non-steroidal estrogenreceptor modulators (e.g. raloxifene, LY353381 (SERM3) and LY357489);steroidal estrogen receptor modulators (e.g. ICI-182,780). Aromataseinhibitors include steroidal aromatase inhibitors and non-steroidalaromatase inhibitors. Steroidal aromatase inhibitors include, but arenot limited to, such exemestane. Non-steroidal aromatase inhibitorsinclude, but are not limited to, as anastrozole, and letrozole.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is administered in combination with a CDK 4/6inhibitor. In some embodiments, the CDK 4/6 inhibitor is palbociclib(PD-0332991), ribociclib (LEE011) or LY283519. In some embodiments, theCDK 4/6 inhibitor is LEE011. In some embodiments, ribociclib (LEE011) isadministered at a dose of about 10 mg per day to about 1000 mg per day.In some embodiments, LEE011 is administered at a dose of about 400 mgper day, about 500 mg per day or about 600 mg per day. In someembodiments, the daily dose of LEE011 is orally administered. In someembodiments, the daily dose of ribociclib (LEE011) is orallyadministered once a day for three weeks followed by a one week drugholiday where ribociclib (LEE011) is not administered.

In some embodiments, a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is administered in combination with aphosphoinositide 3-kinase (PI3K)/mTOR pathway inhibitor. In someembodiments, the a phosphoinositide 3-kinase (PI3K)/mTOR pathwayinhibitor is everolimus, temsirolimus, BEZ235 (dactolisib), BYL719(alpelisib), GDC0032 (taselisib), BKM120 (buparlisib), BGT226, GDC0068(ipatasertib), GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128(MLN0128), INK1117, OSI-027, CC-223, AZD8055, SAR245408, SAR245409,PF04691502, WYE125132, GSK2126458, GSK-2636771, BAY806946, PF-05212384,SF1126, PX866, AMG319, ZSTK474, Cal101 (idelalisib), PWT33597, CU-906,AZD-2014 or CUDC-907. In some embodiments, the phosphoinositide 3-kinase(PI3K)/mTOR pathway inhibitor is everolimus. In some embodiments,everolimus is administered at a dose of about 1 mg per day to about 20mg per day. In some embodiments, everolimus is administered at a dose ofabout 2.5 mg per day, about 5 mg per day, or about 10 mg per day. Insome embodiments, the daily dose of everolimus is administered once aday. In some embodiments, the phosphoinositide 3-kinase (PI3K)/mTORpathway inhibitor is BKM120 (buparlisib). In some embodiments, BKM120(buparlisib) is administered at a dose of about 5 mg per day to about500 mg per day. In some embodiments, BKM120 is administered at a dose ofabout 50 mg per day to about 100 mg per day. In some embodiments, BKM120is administered at a dose of about 100 mg per day. In some embodiments,the daily dose of BKM120 is administered once a day. In someembodiments, the phosphoinositide 3-kinase (PI3K)/mTOR pathway inhibitoris BYL719. In some embodiments, BYL719 is administered at a dose ofabout 25 mg per day to about 1000 mg per day. In some embodiments,BYL719 is administered at a dose of about 250 mg per day or about 350 mgper day. In some embodiments, the daily dose of BYL719 is administeredonce a day.

Metabolites of Compounds of Formula I

Also falling within the scope of this invention are the in vivometabolic products of Formula I described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, the inventionincludes metabolites of compounds of Formula I, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof.

Metabolite products typically are identified by preparing aradiolabelled (e g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. In one embodiment, the kitcomprises a container comprising a compound of Formula I, or astereoisomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof. The kit may further comprise a labelor package insert on or associated with the container. The term “packageinsert” is used to refer to instructions customarily included incommercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, for example, bottles, vials, syringes,blister pack, etc. The container may be formed from a variety ofmaterials such as glass or plastic. The container may hold a compound ofFormula I or a formulation thereof which is effective for treating thecondition and may have a sterile access port (for example, the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). At least one active agent in thecomposition is a compound of Formula I. The label or package insertindicates that the composition is used for treating the condition ofchoice, such as cancer. In addition, the label or package insert mayindicate that the patient to be treated is one having a disorder such asa hyperproliterative disorder, neurodegeneration, cardiac hypertrophy,pain, migraine or a neurotraumatic disease or event. In one embodiment,the label or package inserts indicates that the composition comprising acompound of Formula I can be used to treat a disorder resulting fromabnormal cell growth. The label or package insert may also indicate thatthe composition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula I and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I, such as tablets or capsules. Sucha kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula I contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound with anti-hyperproliferative activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Preparation of Formula I Compounds

Compounds of Formula I may be synthesized by synthetic routes thatinclude processes analogous to those well-known in the chemical arts,particularly in light of the description contained herein, and those forother heterocycles described in; Comprehensive Heterocyclic ChemistryII, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; LiebigsAnnalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990),each of which are expressly incorporated by reference. Startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), orBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database).

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing Formula I compoundsand necessary reagents and intermediates are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995) and subsequent editionsthereof.

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

The Examples provide exemplary methods for preparing Formula Icompounds. Those skilled in the art will appreciate that other syntheticroutes may be used to synthesize the Formula I compounds. Althoughspecific starting materials and reagents are depicted and discussed inthe Figures and Examples, other starting materials and reagents can beeasily substituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the exemplary compounds prepared by thedescribed methods can be further modified in light of this disclosureusing conventional chemistry well known to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

In the methods of preparing Formula I compounds, it may be advantageousto separate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified to the desired degree of homogeneity by thetechniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like. Selection of appropriate methodsof separation depends on the nature of the materials involved, such as,boiling point and molecular weight in distillation and sublimation,presence or absence of polar functional groups in chromatography,stability of materials in acidic and basic media in multiphaseextraction, and the like.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including; (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See; “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Formula I compounds can be prepared by the General Procedures of Schemes1-7.

Scheme 1 shows para-hydroxy benzaldehyde intermediate 1 reacted withtert-butyl 3-iodoazetidine-1-carboxylate to give exemplary tert-butyl3-(4-formylphenoxy)azetidine-1-carboxylate intermediate 2. An exemplaryintermediate 1 is 2,6-difluoro-4-hydroxybenzaldehyde. Cyclization of 2with bicyclic amines 3 gives tricyclic,tetrahydro-pyrido[3,4-b]indol-1-yl azetidine intermediate 4. Acidicdeprotection of 4 and alkylation of 5 gives tricyclic,tetrahydro-pyrido[3,4-b]indol-1-yl azetidine intermediate 6.

Scheme 2 shows para-iodo benzaldehyde intermediates 7, such as2,6-difluoro-4-iodobenzaldehyde, are cyclized with bicyclic amines 3gives tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl iodophenylintermediate 8. Reaction of 8 with alcohol 9 gives tricyclic,tetrahydro-pyrido[3,4-b]indol-1-yl intermediate 10.

Scheme 3 shows reaction of amine 11 with an alkylating reagent, in whichthe leaving group could be an iodide, or a bromide, or a triflate, ledto intermediate 12. Alternatively, the amine 11 could also react with analdehyde or ketone to give intermediate 12 through reductive aminationreaction. Condensation of intermediate 12 with an aldehyde then producedintermediate 13. The iodide or bromide on the X¹ group of Cy could thenbe coupled with an alcohol, or an amine, or a sulfide, or an olefinthrough a Pd- or Cu-catalyzed Ullman, or Buchwald, or Heck reaction togive target 14. Alternatively, the protected phenol (OP) on group Cycould be deprotected, and the resulting phenol could be further coupledwith an alcohol through a Mitsunobu reaction. Alternatively, the phenolcould also be alkylated, with an iodide, or a bromide, or a chloride, ora triflate, or a mesylate, to give tricyclic,tetrahydro-pyrido[3,4-b]indol-1-yl intermediate 14.

Scheme 4 shows Pictet-Spengler cyclization of amine 11 with an aldehydeleads to intermediate 15 where X¹ is iodide or bromide. Reaction ofamine 15 with an acid chloride produces amide 16. The iodide or bromideX¹ group on Cy could then be coupled with an alcohol, or an amine, or asulfide, or an olefin through a Pd- or Cu-catalyzed Ullman, or Buchwald,or Heck reaction to give intermediate 17. Alternatively, the protectedphenol (OP) on group Cy of 16 can be deprotected, and the resultingphenol could be further coupled with an alcohol through a Mitsunobureaction to give 17. Alternatively, the phenol (OH) can be alkylated,with an iodode, a bromide, a chloride, a triflate, or a mesylate, togive tricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl amide intermediate17.

Scheme 5 shows amine 15 can react with a sulfonyl chloride to givesulfonamide 18, which can be converted by Pd- or Cu-catalyzed Ullman,Buchwald, or Heck reaction or by Mitsunobu or alkylation reactions totricyclic, tetrahydro-pyrido[3,4-b]indol-1-yl sulfonamide intermediate19.

Scheme 6 shows amine 15 can react with an alkylating agent (R⁵-X) togive intermediate 13. Alternatively amine 15 can react with an aldehydeor ketone and a reducing agent, such as sodium cyanoborohydride, to giveintermediate 13.

Scheme 7 shows the general synthetic route for tryptamine 23. Asubstituted indole 20 is transformed to aldehyde 21, under Vilsmeierreaction conditions. Aldol reaction of aldehyde 21 with nitroethanegives compound 22. Reduction of 22 with lithium aluminum hydride thenyields tryptamine 23.

EXAMPLES Example 101(1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole101 Step 1: 3-(3,5-Difluoro-4-formyl-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester 101c

To a solution of 2,6-difluoro-4-hydroxy-benzaldehyde 101a (CAS No.:532967-21-8, 600 mg, 3.79 mmol) in N,N-dimethyl form amide (25 mL) underargon were added cesium carbonate (3.09 g, 9.48 mmol) and1-Boc-3-iodoazetidine 101b (CAS No.: 254454-54-1, 2.68 g, 9.48 mmol).The resulting mixture was heated at 150° C. under microwave heating for1 h. The reaction mixture was allowed to cool to ambient temperature,the solid removed by filtration, the filter cake was washed with tolueneand the filtrate was concentrated in vacuo. The residue was partitionedbetween EtOAc and water, the organic phase was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was adsorbed onto HMN diatomaceous earth (Isolute®, Biotage) andpurified by silica gel chromatography (mobile phase: cyclohexane/ethylacetate, gradient 0% to 30%) to afford 101c as a yellow oil (1.10 g,93%). ¹H NMR (300 MHz, CDCl₃): δ 10.20 (s, 1H), 6.35 (m, 2H), 4.94-4.86(m, 1H), 4.34 (ddd, J=1.1, 6.4, 9.8 Hz, 2H), 4.05-3.98 (m, 2H), 1.45 (s,9H).

Step 2:(2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-amine101d

Compound 101d was prepared according to WO 2014/191726, page 78

Step 3:3-{3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl]-phenoxy}-azetidine-1-carboxylicAcid tert-butyl ester 101e

To a solution of(2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-amine101d, prepared according to WO 2014/191726, page 78 (540 mg, 2.17 mmol)in toluene (8 mL) under argon were added3-(3,5-difluoro-4-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butylester 101c (818 mg, 2.61 mmol) and acetic acid (249 μL, 4.34 mmol). Themixture was heated at 80° C. in a sealed tube for 4 h protected fromlight. The reaction mixture was allowed to cool to room temperature (RT)and concentrated in vacuo. The residue was partitioned between ethylacetate (EtOAc) and saturated sodium hydrogen carbonate solution. Theorganic phase was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was adsorbed ontoHMN diatomaceous earth and purified by silica gel chromatography (mobilephase: cyclohexane/ethyl acetate, gradient 0% to 20%) to afford 101e asan off-white solid (1.10 g, 90%). ¹H NMR (300 MHz, CDCl₃): δ 7.54-7.49(m, 1H), 7.39 (s, 1H), 7.25-7.19 (m, 1H), 7.15-7.05 (m, 2H), 6.28-6.21(m, 2H), 5.20 (s, 1H), 4.84-4.76 (m, 1H), 4.33-4.24 (m, 2H), 4.02-3.94(m, 2H), 3.69-3.61 (m, 1H), 3.12-3.02 (m, 1H), 2.84 (dd, J=15.1, 20.0Hz, 1H), 2.65-2.56 (m, 1H), 2.38 (dd, J=14.9, 24.7 Hz, 1H), 1.45 (s,9H), 1.28-1.08 (m, 9H); LCMS: 544.5 [M+H]⁺.

Step 4:(1R,3R)-1-[4-(Azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline101f

To a mixture of3-{3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl]-phenoxy}-azetidine-1-carboxylicacid tert-butyl ester 101e (840 mg, 1.54 mmol) in dichloromethane (10mL) under argon was added TFA (1.75 mL, 23.1 mmol) dropwise and themixture was stirred, protected from light, at RT for 3 h. The reactionmixture was concentrated in vacuo and purified using an SCX-2 cartridge(mobile phase: dichloromethane/methanol 1:1 then 2N ammonia inmethanol). Appropriate fractions were combined and evaporated to afford101f as an off-white solid (54 mg, 8%). ¹H NMR (300 MHz, CDCl₃): δ7.54-7.49 (m, 1H), 7.41 (s, 1H), 7.25-7.20 (m, 1H), 7.13-7.07 (m, 2H),6.30-6.22 (m, 2H), 5.19 (s, 1H), 4.96-4.90 (m, 1H), 3.97-3.91 (m, 2H),3.83-3.78 (m, 2H), 3.71-3.60 (m, 1H), 3.12-3.03 (m, 1H), 2.85 (dd,J=15.1, 19.6 Hz, 1H), 2.64-2.55 (m, 1H), 2.38 (dd, J=15.1, 25.2 Hz, 1H),1.82 (br. s, 1H), 1.27-1.07 (m, 9H); LCMS: 442.5 [M−H]⁻.

Step 5: To a mixture of(7R,3R)-1-[4-(azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline101f (54 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) under argon wereadded 1-bromo-3-fluoropropane (16 μL, 0.16 mmol; CAS No. 352-91-0) andethyldiisopropylamine (12 μL, 0.24 mmol). The reaction mixture wasstirred at RT for 48 h protected from light. The reaction mixture waspoured into a mixture of ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over Na₂SO₄, filtered, andthe filtrate concentrated under reduced pressure. The crude product waspurified by silica gel chromatography (mobile phase:dichloromethane/methanol, gradient 0% to 5%) and then using a C18cartridge (acetonitrile, water, formic acid). Appropriate fractions werecombined and evaporated to give 101 as a yellow solid (27 mg, 8%). ¹HNMR (400 MHz, CDCl₃): δ 11.12 (br s., 1H), 8.27 (s, 1.3H, formic acid),7.53-7.47 (m, 2H), 7.24-7.20 (m, 1H), 7.13-7.08 (m, 2H), 6.31-6.25 (m,2H), 5.20 (s, 1H), 4.96-4.89 (m, 1H), 4.56 (dd, J=5.6, 5.6 Hz, 1H), 4.44(dd, J=5.6, 5.6 Hz, 1H), 4.33-4.24 (m, 2H), 3.64 (dd, J=4.8, 11.1 Hz,1H), 3.49-3.47 (m, 1H), 3.07-2.97 (m, 3H), 2.84 (dd, J=15.0, 20.3 Hz,1H), 2.64-2.58 (m, 1H), 2.38 (dd, J=15.0, 24.5 Hz, 1H), 1.99-1.83 (m,2H), 1.27-1.08 (m, 9H); LCMS: 504.3 [M+H]⁺.

Example 102(1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole102 Step 1:(1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline102b

To a solution of(2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-amine101d, prepared according to WO 2014/191726, page 78, (50 mg, 0.20 mmol)in toluene (170 μL) under argon was added2,6-difluoro-4-iodo-benzaldehyde 102a (CAS No.: 1160573-10-3, 65 mg,0.24 mmol) followed by acetic acid (23 μL, 0.40 mmol). The resultingmixture was stirred at 80° C. in a sealed tube for 5 h then allowed tocool to RT. The mixture was purified on an SCX-2 cartridge (mobilephase: dichloromethane/methanol 9:1 then 2 N ammonia in methanol).Appropriate fractions were combined, evaporated and the crude productwas purified by silica gel chromatography (mobile phase:cyclohexane/ethyl acetate, gradient 0% to 30%) to afford 102b as ayellow solid (89 mg, 89%). ¹H NMR (400 MHz, CDCl₃): δ 7.54-7.50 (m, 1H),7.39 (s, 1H), 7.25-7.21 (m, 3H), 7.16-7.08 (m, 2H), 5.26 (s, 1H),3.67-3.60 (m, 1H), 3.06 (ddd, J=1.5, 4.9, 15.2 Hz, 1H), 2.86 (dd,J=15.2, 21.5 Hz, 1H), 2.61 (ddd, J=1.5, 4.4, 15.2 Hz, 1H), 2.39 (dd,J=15.2, 24.0 Hz, 1H), 1.29-1.15 (m, 6H), 1.10 (d, J=6.4 Hz, 3H); LCMS:497.0 [M−H]⁻.

Step 2: A mixture of(1R,3R)-1-(2,6-Difluoro-4-iodo-phenyl)-2-(2-fluoro-2-methyl-propyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline102b (82 mg, 0.16 mmol), 2-(3-fluoromethyl-azetidin-1-yl)-ethanol 102c,prepared according to WO 2013/090836, page 124 (44 mg, 0.33 mmol; CASNo.: 1443984-69-7, WO 2013/090836), copper iodide (6.2 mg, 0.03 mmol),and potassium carbonate (68 mg, 0.49 mmol) in butyronitrile (600 μL) wasdegassed with three vacuum/argon cycles. The reaction mixture was heatedat 135° C. for 24 h, allowed to cool to room temperature and dilutedwith ethyl acetate. The solid was removed from the reaction mixture byfiltration through Celite and the solid was washed with ethyl acetate.The combined filtrate was washed with water (three times) and brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude product was purified by silica gel chromatography (mobilephase: 0-7% methanol/dichloromethane). Appropriate fractions werecollected and evaporated to give 102 as a yellow solid (17.2 mg, 21%).¹H NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 7.39 (d, J=73 Hz, 1H), 7.18(d, J=7.8 Hz, 1H), 7.01-6.91 (m, 2H), 6.64 (d, J=11.2 Hz, 2H), 5.11 (s,1H), 4.56 (d, J=5.9 Hz, 1H), 4.44 (d, J=5.4 Hz, 1H), 3.92 (s, 2H),3.54-3.47 (m, 2H), 3.06-2.66 (m, 6H), 2.59-2.53 (m, 2H, partially underDMSO-d6), 2.40-2.27 (m, 2H), 1.25-1.09 (m, 6H), 1.04 (d, J=6.4 Hz, 3H);LCMS: 502.3 [M−H]⁻.

Example 1031-((1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-methylpropan-1-one103 Step 1:(1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole103b

To a microwave vial was added (2R)-1-(1H-indol-3-yl)propan-2-amine 103a(710 mg, 3.67 mmol), followed by 2,6-difluoro-4-iodo-benzaldehyde (1.1g, 4.03 mmol) and acetonitrile (2.6 mL). The reaction was placed under anitrogen atmosphere and TFA (0.5 mL, 7.0 mmol) was added. Then thereaction was heated to 130° C. in a microwave for 1 h and then quenchedwith a saturated aq. NaHCO₃ solution. The mixture was extracted DCM(3×100 mL), dried with MgSO₄, filtered and concentrated. The crudeproduct was purified by flash column chromatography over silica gel(0-100% EtOAc/Hexanes) to yield 103b (450 mg, 29%). ¹H NMR (400 MHz,deuterochloroform-d): δ 7.60-7.48 (m, 2H), 7.27 (d, J=7.3 Hz, 2H),7.17-7.08 (m, 2H), 5.63 (s, 1H), 3.45 (dq, J=12.7, 6.2 Hz, 1H), 2.99(ddd, J=15.5, 4.6, 1.3 Hz, 1H), 2.52 (ddd, J=15.5, 7.3, 1.8 Hz, 1H),1.29 (d, J=6.5 Hz, 3H).

Step 2:1-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-methylpropan-1-one103c

To a round-bottom flask (RBF) was added(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole103b (50 mg, 0.12 mmol), followed by sodium bicarbonate (50 mg, 0.59mmol), and chloroform (0.8 mL). 2-Methylpropanoyl chloride (31 mg,0.2947 mmol) was added and the reaction was heated to 45° C. for 1 h(hour). Diisopropylethylamine (Hunig's base, 0.1 mL, 0.59 mmol) wasadded and the reaction was stirred until LC-MS indicated that thestarting materials were consumed. Aqueous saturated solution (10 mL) ofsodium bicarbonate was added. The reaction mixture is then extractedwith DCM (3×50 mL), dried over MgSO₄, filtered and concentrated. Crudeproduct was purified by flash column chromatography on silica gel(0-100% EtOAc/Hexanes) to give 103c (51 mg, 88%). ¹H NMR (400 MHz,DMSO-d₆): δ 10.74 (s, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.39 (d, J=9.2 Hz,2H), 7.24 (dt, J=8.0, 1.0 Hz, 1H), 7.01 (dddd, J=26.4, 8.0, 7.0, 1.2 Hz,2H), 6.10 (s, 1H), 4.88-4.71 (m, 1H), 3.17 (dd, J=14.9, 5.6 Hz, 1H),3.03 (p, J=6.6 Hz, 1H), 2.84 (d, J=15.2 Hz, 1H), 1.12 (d, J=6.5 Hz, 2H),1.06-0.92 (m, 6H).

Step 3: To a 5 mL microwave vial was added1-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-methyl-propan-1-one103c (51 mg, 0.10 mmol), followed by2-[3-(fluoromethyl)azetidin-1-yl]ethanol 102c, prepared according to WO2013/090836, page 124 (27 mg, 0.21 mmol), copper iodide (8 mg, 0.04mmol), potassium carbonate (43 mg, 0.31 mmol). The vial was sealed andbutyronitrile (0.7 mL) was added. The reaction was then heated to 135°C. overnight and then cooled to room temperature. The reaction mixturewas then filtered through Celite, eluting with EtOAc. The combinedfiltrate was then concentrated and purified by reverse phase HPLC toyield 103 (16 mg, 31%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H),7.51-7.39 (m, 1H), 7.32-7.22 (m, 1H), 7.09-6.90 (m, 2H), 6.51 (d, J=11.0Hz, 2H), 6.11 (s, 1H), 4.89-4.71 (m, 1H), 4.55 (d, J=6.1 Hz, 1H), 4.43(d, J=6.0 Hz, 1H), 3.94 (q, J=5.4 Hz, 2H), 3.59-3.38 (m, 2H), 3.24-3.18(m, 2H), 3.04-2.97 (m, 2H), 2.87-2.74 (m, 4H), 1.12 (d, J=6.4 Hz, 3H),0.98 (dd, J=10.3, 6.7 Hz, 6H); LCMS: 500.3 [M+H]⁺

Example 1041-((1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-one104 Step 1:1-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-one104a

To a round bottom flask was added(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole103b (100 mg, 0.24 mmol), followed by 2-fluoro-2-methyl-propanoylchloride (0.59 mL of a 1 M solution in CHCl₃, prepared from the reactionof the corresponding acid with oxalyl chloride), sodium bicarbonate (99mg, 1.2 mmol) and chloroform (1.6 mL). Then the reaction was then heatedto 45° C. for 1 h and then Hunig's base (0.2 mL, 1.2 mmol) was added.The reaction was stirred until monitoring the reaction by LC-MSindicated that all starting materials were consumed. The reaction wasquenched with a saturated aqueous solution of sodium bicarbonate. Themixture was then extracted with DCM (3×50 mL), dried with MgSO₄,filtered and concentrated. The resulting crude product was purified bysilica gel column chromatography (0-100% EtOAC/Hexanes) to give 104a (95mg, 79%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.54-7.31 (m, 3H), 7.28-7.21 (m,1H), 7.04 (ddd, J=8.1, 7.1, 1.3 Hz, 1H), 6.98 (td, J=7.5, 7.0, 1.1 Hz,1H), 6.08 (s, 1H), 5.14 (s, 1H), 3.14 (dd, J=15.4, 4.6 Hz, 1H), 2.81 (d,J=15.2 Hz, 1H), 1.51 (dd, J=35.4, 21.8 Hz, 6H), 1.17 (dt, J=3.1 Hz, 3H);LCMS: 513.0 [M+H]⁺.

Step 2: To a 5 mL microwave vial was added1-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-one104a (29 mg, 0.056 mmol), followed by2-[3-(fluoromethyl)azetidin-1-yl]ethanol (15 mg, 0.11 mmol), copperiodide (4 mg., 0.023 mmol), potassium carbonate (24 mg, 0.17 mmol), andbutyronitrile (0.37 mL). The solution was degassed for 5 min and thenheated to 135° C. overnight. When monitoring the reaction by LC-MSindicated that all starting materials were consumed, the crude mixturewas cooled to room temperature, filtered through Celite®. The Celiteplug was further washed with EtOAc, and combined filtrate wasconcentrated and purified by reverse phase HPLC to give 104 (9 mg, 31%).¹H NMR (400 MHz, DMSO-d₆, 350K): δ 10.69 (s, 1H), 7.54-7.38 (m, 1H),7.31-7.17 (m, 1H), 7.00 (dtd, J=24.8, 7.1, 1.2 Hz, 2H), 6.55 (d, J=12.0Hz, 1H), 6.03 (s, 1H), 5.21-5.05 (m, 1H), 4.54 (d, J=6.2 Hz, 1H), 4.42(d, J=6.2 Hz, 1H), 3.87 (t, J=5.4 Hz, 2H), 3.30-3.25 (m, 2H), 3.15 (dd,J=15.3, 4.7 Hz, 1H), 2.96 (t, J=6.5 Hz, 2H), 2.79 (d, J=15.1 Hz, 1H),2.75-2.62 (m, 3H), 1.55 (d, J=21.8 Hz, 2H), 1.45 (d, J=21.8 Hz, 2H),1.15 (d, J=6.4 Hz, 2H); LCMS: 518.2 [M+H]⁺.

Example 105(1R,3R)-1-(4-(2-(3-(difluoromethyl)azetidin-1-yl)ethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole105 Step 1: 2-(3,5-difluoro-4-formylphenoxy)ethyl acetate 105a

A solution of 2,6-difluoro-4-hydroxy-benzaldehyde (CAS No.: 532967-21-8,300 mg, 1.89 mmol) and 2-bromo-ethylacetate (CAS No.: 927-68-4, 0.22 mL,2 mmol) in acetonitrile (5 mL) and N,N-dimethylformamide (1 mL) washeated at 80° C. for 24 h. A further portion of 2-bromo-ethylacetate(0.11 mL, 1 mmol) was added, and heating continued at 80° C. foradditional 30 h. The reaction mixture was allowed to cool to ambienttemperature. The residue was partitioned between EtOAc and a saturatedsolution of sodium bicarbonate. The aqueous layer was extracted withfurther portions of EtOAc. The combined organic layer was separated,dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified by silica gel column chromatography (mobile phase:cyclohexane/ethyl acetate, gradient 0% to 33%) to afford 105a as a whitepowder (213 mg, 45%). ¹H NMR (300 MHz, CDCl₃): δ 10.20 (s, 1H), 6.51 (d,J=10.4 Hz, 2H), 4.44 (t, J=4.7 Hz, 2H), 4.22 (t, J=4.7 Hz, 2H), 2.11 (s,3H).

Step 2:2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethylacetate 105b

To a solution of(2-fluoro-2-methyl-propyl)-[(R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-amine101d (213 mg, 0.86 mmol) and 2-(3,5-difluoro-4-formylphenoxy)ethylacetate 105a (210 mg, 0.86 mmol) in toluene (1 mL) under argon, wasadded glacial acetic acid (0.1 mL, 1.72 mmol). The vessel was sealed,and the reaction mixture was heated at 80° C. for 16 h. The reactionmixture was allowed to cool to ambient temperature. The residue waspartitioned between dichloromethane and a saturated solution of sodiumbicarbonate. The aqueous layer was extracted with further portions ofdichloromethane. The combined organic layer was separated, dried overMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by silica gel chromatography (mobile phase: cyclohexane/ethylacetate, gradient 0% to 20%) to afford 105b as a white foam (323 mg,80%). ¹H NMR (300 MHz, CDCl₃): δ 7.54-7.49 (m, 1H), 7.38 (s, 1H),7.24-7.19 (m, 1H), 7.14-7.07 (m, 2H), 6.42 (dd, J=13, 3 Hz, 2H), 5.19(s, 1H), 4.40 (t, J=4.7 Hz, 2H), 4.12 (t, J=4.7 Hz, 2H), 3.70-3.62 (m,1H), 3.13-3.04 (m, 1H), 2.92-2.79 (dd, J=19, 15 Hz, 1H), 2.65-2.55 (m,1H), 2.46-2.31 (dd, J=25.0, 15.0 Hz, 1H), 2.10 (s, 3H), 1.24 (d, J=11.0Hz, 3H), 1.17 (d, J=11.3 Hz, 3H), 1.1 (d, J=6.5 Hz, 3H).

Step 3:2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethanol105c

To a solution of2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethylacetate 105b (320 mg, 0.675 mmol) in THF/MeOH (2/1, 6 mL) was addedsodium hydroxide (1 N, 4 mL). The reaction mixture was heated at 70° C.for 45 min. The reaction mixture was allowed to cool to ambienttemperature, and the solvent was removed in vacuo. The residue waspartitioned between dichloromethane and water. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated in vacuo, toafford 105c as a white foam (264 mg, 91%). LCMS: 431.2 [M−H]⁻.

Step 4:(1R,3R)-1-(4-(2-bromoethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole105d

To a solution of2-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenoxy)ethanol105c (130 mg, 0.3 mmol) in DCM (2.5 mL) were added triphenylphosphine(94 mg, 0.36 mmol) and carbon tetrabromide (120 mg, 0.36 mmol). Thereaction mixture was stirred at room temperature for 1 h, then thesolvent was removed in vacuo. The crude product was purified by silicagel column chromatography (mobile phase: cyclohexane/ethyl acetate,gradient 0% to 20%) to afford 105d as a white foam (142 mg, 95%). ¹H NMR(300 MHz, CDCl₃): δ 7.54-7.49 (m, 1H), 7.38 (s, 1H), 7.25-7.19 (m, 1H),7.15-7.07 (m, 2H), 6.42 (dd, J=13.0, 3.0 Hz, 2H), 5.20 (s, 1H), 4.24 (t,J=4.7 Hz, 2H), 3.72-3.59 (m, 3H), 3.12-3.03 (m, 1H), 2.92-2.79 (dd,J=19.4, 15.0 Hz, 1H), 2.64-2.56 (m, 1H), 2.46-2.31 (dd, J=25.0, 15.0 Hz,1H), 1.24 (d, J=12.1 Hz, 3H), 1.17 (d, J=12 Hz, 3H), 1.10 (d, J=6.5 Hz,3H).

Step 5: To a solution of(1R,3R)-1-(4-(2-bromoethoxy)-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole105d (62 mg, 0.125 mmol) in acetonitrile (1 mL) were addedN,N-diisopropylethylamine (0.064 mL, 0.375 mmol) and3-(difluoromethyl)azetidine hydrochloride (CAS 1354792-76-9, 27 mg,0.187 mmol). The reaction mixture was stirred at room temperature for 1h, then at 45° C. for 4 h. The reaction mixture was allowed to cool toambient temperature. The residue was partitioned between EtOAc andwater. The aqueous layer was extracted with further portions of EtOAc.The combined organic layers were separated, dried over MgSO₄, filteredand concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (mobile phase: dichloromethane/methanol, gradient0% to 2.5%) to afford 105 as an off-white solid (40 mg, 62%). ¹H NMR(300 MHz, CDCl₃): δ 7.54-7.49 (m, 1H), 7.38 (s, 1H), 7.24-7.19 (m, 1H),7.14-7.06 (m, 2H), 6.38 (dd, J=13.3, 3 Hz, 2H), 6.17-5.76 (dt, J=56.0,5.1 Hz, 1H), 5.18 (s, 1H), 3.90 (t, J=5.3 Hz, 2H), 3.71-3.63 (m, 1H),3.46 (t, J=7.8 Hz, 2H), 3.27 (t, J=6.7 Hz, 2H), 3.13-3.04 (m, 1H),2.92-2.79 (m, 3H), 2.64-2.55 (m, 1H), 2.45-2.30 (dd, J=25.6, 14.9 Hz,1H), 1.23 (d, J=10.3 Hz, 3H), 1.16 (d, J=12 Hz, 3H), 1.09 (d, J=6.5 Hz,3H); LCMS: 520.4 [M−H]⁻.

Compounds 106-125 were prepared by the procedures described herein andcharacterized by LCMS [M+H]⁺:

106 520.1 107 486.4 108 532.4 109 518.2 110 111 469.2 112 487.3 113498.3 114 514.3 115 500.3 116 486.3 117 486.1 118 500.2 119 500.2 120484.2 121 472.2 122 516.2 123 502.3 124 528.3 125 514.3

Example 126(1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole126 Step 1:(1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2-(methylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

To a 50-mL round-bottom-flask was added(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(50 mg, 0.12 mmol) and chloroform (0.15 M, 0.8 mL). ThenN,N-diisopropylethylamine (0.06 mL, 0.35 mmol) and methanesulfonylchloride (0.014 mL, 0.18 mmol) were added sequentially. The reaction wasthen heated to 45° C. and monitored until LCMS indicated completeconsumption of the starting materials. The reaction was cooled to roomtemperature, quenched with the addition of saturated aq. NH₄Cl,extracted with DCM (3×50 mL), dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash columnchromatography over silica gel, eluting with 0-50% iPrOAc/Heptanes toyield the title compound (40 mg, 68% yield). ¹H NMR (400 MHz, DMSO-d₆) δ10.78 (s, 1H), 7.54 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.22 (d,J=8.1 Hz, 1H), 7.05 (ddd, J=8.2, 7.1, 1.2 Hz, 1H), 7.02-6.95 (m, 1H),6.18 (s, 1H), 4.43 (q, J=5.6, 5.0 Hz, 1H), 3.09-2.99 (m, 1H), 2.83 (s,4H), 1.31 (d, J=6.6 Hz, 3H). LCMS: 503.0 [M+H]⁺.

Step 2: To a 5 mL vial was added(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2-methylsulfonyl-1,3,4,9-tetrahydropyrido[3,4-b]indole(40 mg, 0.08 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (21 mg,0.16 mmol), cuprous iodide (6 mg, 0.032 mmol), potassium carbonate (33mg, 0.24 mmol) and butyronitrile (0.5 mL). The solution was degassed for5 min and then heated to 135° C. overnight. Once monitoring the reactionby LCMS indicated reaction was complete, the reaction mixture wasfiltered through Celite, eluting with EtOAc. The filtrate wasconcentrated and purified by reverse phase HPLC to yield 126 (6 mg, 15%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (s, 1H), 7.43 (d, J=7.7 Hz,1H), 7.24-7.20 (m, 1H), 7.04 (ddd, J=8.2, 7.0, 1.4 Hz, 1H), 6.97 (td,J=7.4, 1.1 Hz, 1H), 6.73-6.64 (m, 2H), 6.15 (s, 1H), 4.55 (d, J=6.2 Hz,1H), 4.45-4.35 (m, 2H), 3.93 (t, J=5.4 Hz, 2H), 3.30-3.28 (m, 2H),3.03-2.95 (m, 3H), 2.77 (s, 3H), 2.74-2.65 (m, 4H), 1.33 (dd, J=6.8, 2.1Hz, 3H). LCMS: 508.2 [M+H]⁺.

Example 145N-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amineStep 1:(1R,3R)-1-(4-Bromo-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-&]indole

To a solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-2-fluoro-2-methylpropan-1-amine(500 mg, 2.01 mmol) in toluene (6 mL) was added4-bromo-2,6-difluorobenzaldehyde (490 mg, 2.21 mmol) and acetic acid(0.58 mL, 10.2 mmol). The reaction mixture was stirred at 80° C. for 16hours. After being cooled to room temperature, the solution wasconcentrated and the residue was diluted with EtOAc (40 mL), washed withsaturated aqueous NaHCO₃ (10 mL) and water (20 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica (solvent gradient: 0-6% EtOAc inpetroleum ether) to afford the title compound (800 mg, 88%) as a lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J=7.2 Hz, 1H), 7.41 (s,1H), 7.24 (d, J=7.2 Hz, 1H), 7.16-7.09 (m, 2H), 7.06 (d, J=8.0 Hz, 2H),5.27 (s, 1H), 3.73-3.54 (m, 1H), 3.09-3.05 (m, 1H), 2.95-2.76 (m, 1H),2.64-2.60 (m, 1H), 2.47-2.33 (m, 1H), 1.30-1.17 (m, 6H), 1.11 (d, J=6.4Hz, 3H).

Step 2: t-Butyl3-((3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate

A mixture of(1R,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(From Step 1, 800.0 mg, 1.77 mmol), BINAP (110.4 mg, 0.18 mmol),Pd₂(dba)₃ (162.3 mg, 0.18 mmol), t-BuONa (511.0 mg, 5.32 mmol) andt-butyl 3-aminoazetidine-1-carboxylate (457.9 mg, 2.66 mmol) in toluene(10 mL) was stirred at 110° C. under N₂ atmosphere for 16 hours. Thereaction mixture was concentrated and was purified with silica gelcolumn (0-5% methanol in DCM) to afford the title compound (900 mg, 94%)as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J=6.4 Hz, 1H), 7.43(s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.13-7.05 (m, 2H), 5.97 (d, J=11.2 Hz,2H), 5.14 (s, 1H), 4.37-4.21 (m, 3H), 4.20-4.01 (m, 1H), 3.78-3.60 (m,3H), 3.12-3.07 (m, 1H), 2.96-2.77 (m, 1H), 2.63-2.57 (m, 1H), 2.48-2.33(m, 1H), 1.45 (s, 9H), 1.25-1.17 (m, 6H), 1.10 (d, J=6.0 Hz, 3H)

Step 3:N-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine

To a mixture of t-butyl3-((3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate(From Step 2, 0.9 g, 1.66 mmol) in DCM (5 mL) was added TFA (1.8 mL,24.88 mmol) at −20° C. The resulting mixture was stirred at 0° C. for 16hours. Aqueous NaHCO₃ solution (80 mL) was added slowly to the reactionmixture and the reaction mixture was then extracted with DCM (100 mL×2).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated to give the title compound (700 mg, 95%) as a brownsolid. The crude product was used for the next step without furtherpurification.

Step 4: To a mixture ofN-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-A]indol-1-yl)phenyl)azetidin-3-amine(From Step 3, 700.0 mg, 1.58 mmol) and N,N-diisopropylethylamine (613.3mg, 4.75 mmol) in N,N-dimethylformamide (10 mL) was added1-bromo-3-fluoropropane (223.0 mg, 1.58 mmol) and the reaction mixturewas stirred at 10° C. for 16 hours. The reaction mixture was purified bycolumn (0-10% MeOH in DCM) and further purified by reverse phasechromatography (acetonitrile 66-96%/0.05% NH₄OH in water) to afford 145(280 mg, 35%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.38 (d, J=7.6Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.03-6.88 (m, 2H), 6.07 (d, J=11.6 Hz,2H), 5.10 (s, 1H), 4.54-4.36 (m, 2H), 4.03-4.01 (m, 1H), 3.79-3.71 (m,2H), 3.69-3.65 (m, 1H), 3.04-3.00 (m, 1H), 2.97-2.91 (m, 2H), 2.87-2.85(m, 1H), 2.62 (t, J=7.6 Hz, 2H), 2.58-2.55 (m, 1H), 2.48-2.32 (m, 1H),1.83-1.67 (m, 2H), 1.20-1.11 (m, 6H), 1.08 (d, J=6.8 Hz, 3H).

Example 154(S)-3-((1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-ol154 Step 1: dimethyl 2-fluoro-2-methylmalonate

To a 500-mL oven-dried round-bottom flask was added sodium hydride (1.15equiv., 21 mmol). The reaction reaction was placed under a nitrogenatmosphere and cooled to 0° C. Then THF (63 mL) was added. To thismixture was added dimethyl 2-methylpropanedioate (5.0 g, 34.2 mmol)dropwise and the reaction mixture was stirred for 30 min. Thenn-fluorobenzenesulfonimide (1.05 equiv., 19.2 mmol) was added in oneportion. The reaction mixture was allowed to warm to room temperatureand the reaction mixture solidified, so additional 50 mL of THF wasadded. After 1.5 h the reaction was quenched with aq. 2 N HCl, dilutedwith EtOAc (500 mL) and was washed with 3×200 mL 2 N HCl. The organicswere separated, dried with MgSO₄, filtered, and concentrated. The crudewhite solid was then taken up in 200 mL heptane, sonicated and filteredthrough Celite. The filtered solids where then washed with 3×200 mLheptane. The combined filtrate was then concentrated to yield crudedesired product (3 g, 53% yield) as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 3.32 (s, 6H), 1.18 (d, J=6.3 Hz, 3H).

Step 2: 2-fluoro-2-methylpropane-1,3-diol

To a 500-mL oven-dried round-bottom flask was added dimethyl2-fluoro-2-methylpropanedioate (3 g, 18.3 mmol) and THF (90 mL). Thereaction mixture was placed under N₂ atmosphere and then cooled to 0° C.Then lithium aluminum hydride solution (1 M in THF, 2.75 equiv., 50.3mmol) was added dropwise and the reaction was warmed to room temperatureover 1 h. The reaction was then cooled to 0° C. again and quenched withaddition of water (2 mL), followed by 15% NaOH aq. sol. (2 mL) and water(4 mL). The slurry was stirred for 15 min, filtered and concentrated todeliver the crude product (1.4 g, 71% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 4.85 (t, J=5.9 Hz, 2H), 3.45 (d, J=5.9 Hz, 2H), 3.41 (d, J=5.9 Hz,2H), 1.22-1.15 (d, 3H).

Step 3: 3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropan-1-ol

To a 500-mL oven-dried round-bottom flask was added2-fluoro-2-methyl-propane-1,3-diol (1.47 g, 1.25 equiv., 13.6 mmol),followed by imidazole (1.11 g, 1.5 equiv., 16.4 mmol),tert-butylchlorodiphenylsilane (3.0 g, 10.9 mmol) and chloroform (136mL). The reaction was stirred overnight and quenched with addition ofsat. NH₄Cl solution (100 mL). The mixture was extracted with DCM (100mL), dried with MgSO₄, filtered and concentrated. The crude mixture waspurified by flash silica gel column chromatography (0-100%iPrOAc/Heptanes) to furnish the desired product (1.26 g, 33% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 7.68-7.60 (m, 4H), 7.51-7.40 (m, 6H), 4.97 (t,J=5.8 Hz, 1H), 3.70 (dd, J=19.4, 1.9 Hz, 2H), 3.52 (ddd, J=18.5, 5.8,1.8 Hz, 2H), 1.28 (d, J=21.8 Hz, 3H), 1.01 (s, 9H).

Step 4: 3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropyltrifluoromethanesulfonate

To a 500-mL oven-dried round-bottom flask was added3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propan-1-ol (1.3 g,3.8 mmol), dichloromethane (63 mL) under a nitrogen atmosphere. Thereaction mixture was then cooled to 0° C. and trifluoromethanesulfonicanhydride (1.27 g, 1.2 equiv., 4.5 mmol) was added dropwise. Thereaction mixture was then stirred for 2 h and then washed with 2 N HCland then sat. NaHCO₃ solution. The organics were separated, then driedwith MgSO₄, and filtered through a silica gel plug eluting with DCM.Then the filtrate was concentrated to dryness to yield the crude desiredproduct (1.8 g, 100% yield) and used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66-7.58 (m, 4H), 7.56-7.41(m, 6H), 5.07-4.81 (m, 2H), 3.88-3.68 (m, 2H), 1.40 (d, J=21.6 Hz, 3H),1.01 (s, 9H).

Step 5:N—((R)-1-(1H-indol-3-yl)propan-2-yl)-3-(tert-butyldiphenylsilyloxy)-2-fluoro-2-methylpropan-1-amine

To a 250-mL oven-dried round-bottom flask was added(2R)-1-(1H-indol-3-yl)propan-2-amine (600 mg, 3.1 mmol),N,N-diisopropylethylamine (0.81 mL, 1.5 equiv., 4.65 mmol) and1,4-dioxane (6 mL) and the reaction mixture was placed under a nitrogenatmosphere. Then[3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propyl]trifluoromethanesulfonate(1.95 g, 1.25 equiv., 3.9 mmol) was added and the reaction mixture washeated to 90° C. When LC-MS indicated the consumption of the startingmaterial, the reaction mixture was quenched with sat aq NaHCO₃ and themixture was extracted with EtOAc (3×200 mL) The combined organics weredried with MgSO₄, filtered and concentrated. Purification by flashsilica gel column chromatography (0-100% EtOAc/Hexanes) delivered thetitle compound (1.2 g, 77% yield). LCMS: 503.3 [M+H]⁺.

Step 6:3-((R)-1-(1H-indol-3-yl)propan-2-ylamino)-2-fluoro-2-methylpropan-1-ol

3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-N-[(1R)-2-(1H-indol-3-yl)-1-methyl-ethyl]-2-methyl-propan-1-amine(1.2 g, 2.4 mmol) was added to 250-mL oven-dried round-bottom flask andthen THF (9.6 mL) and tetrabutylammonium fluoride hydrate (3 mL of a 1 Msolution in THF) was added. The reaction mixture was allowed to stir atroom temperature until LC-MS indicated complete consumption of thestarting materials. The reaction mixture was quenched with the additionof water and extracted with 25% IPA in DCM 5×100 mL. The combinedorganics were then dried with MgSO₄, filtered, and concentrated.Purification by flash column chromatography over silica gel (0-30% 2 NNH₃ in MeOH/DCM) provides the title compound (332 mg, 53% yield). LCMS:265.1 [M+H]⁺.

Step 7:3-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2-fluoro-2-methylpropan-1-ol

To a 100-mL round-bottom flask was added2-fluoro-3-[[(1R)-2-(1H-indol-3-yl)-1-methyl-ethyl]amino]-2-methyl-propan-1-ol(332 mg, 1.26 mmol), 2,6-difluoro-4-iodo-benzaldehyde (370 mg, 1.1equiv., 1.38 mmol), and toluene (5.5 mL). The reaction was placed undera nitrogen atmosphere and acetic acid (2 M) was added. Then the reactionwas allowed to heat to 90° C. for 48 h. The reaction was then quenchedwith sat. aq. solution of NaHCO₃ and vigorously extracted with iPrOAc(5×100 ml). The organics where then dried with MgSO₄, filtered andconcentrated. Purification by flash column chromatography over silicagel (0-100% iPrOAc/heptanes) delivered the title compound (475 mg, 74%yield). LCMS: 515.1 [M+H]⁺.

Step 8: To a 20-mL microwave vial was added3-[(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-ol(400 mg, 0.78 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (518 mg, 5equiv., 3.9 mmol), cuprous iodide (74 mg, 0.5 equiv., 0.39 mmol) andpotassium carbonate (644 mg, 6 equiv., 4.7 mmol). The vial was cappedand the mixture was placed under an atmosphere of nitrogen. Thenbutyronitrile (5.2 mL) was added and the mixture was degassed for 10min. Then reaction mixture was then heated to 135° C. for 16 h, filteredthrough Celite and purified via chiral reverse phase HPLC to yield twodiastereomers. 154 was the second eluting diastereomer (90 mg, 22%yield) 154: ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 7.39 (dd, J=7.4,1.3 Hz, 1H), 7.17 (dd, J=7.6, 1.2 Hz, 1H), 6.96 (dtd, J=20.1, 7.2, 1.3Hz, 2H), 6.72-6.55 (m, 2H), 5.08 (s, 1H), 4.84 (t, J=5.6 Hz, 1H), 4.56(d, J=6.2 Hz, 1H), 4.44 (d, J=6.2 Hz, 1H), 3.92 (t, J=5.4 Hz, 2H), 3.55(q, J=6.0, 5.4 Hz, 1H), 3.03-2.83 (m, 4H), 2.72 (dt, J=13.0, 5.6 Hz,3H), 2.61-2.51 (m, 2H), 2.45-2.30 (m, 1H), 1.15-0.96 (m, 6H). 2 Protonsobscured under the water peak. Chiral SFC: column OX UPC2, isocratic 25%MeOH with 0.1% NH₄OH for 2.5 min. Retention time 1.35 min. LCMS: 520.3[M+H]⁺.

Example 155(2R)-3-[(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2-fluoro-2-methyl-propan-1-ol155

Following the procedures of Example 154, 155 was the first elutingdiastereomer (110 mg, 27% yield). 155. ¹H NMR (400 MHz, DMSO-d₆): δ10.52 (s, 1H), 7.42-7.34 (m, 1H), 7.21-7.14 (m, 1H), 6.96 (dtd, J=20.9,7.1, 1.2 Hz, 2H), 6.69-6.58 (m, 2H), 5.12 (s, 1H), 4.81 (t, J=5.8 Hz,1H), 4.56 (d, J=6.2 Hz, 1H), 4.44 (d, J=6.2 Hz, 1H), 3.93 (t, J=5.4 Hz,2H), 3.46 (ddd, J=18.2, 11.9, 5.7 Hz, 2H), 3.14 (ddd, J=20.4, 11.9, 5.9Hz, 2H), 3.03-2.78 (m, 4H), 2.78-2.64 (m, 3H), 2.58-2.51 (m, 2H),2.47-2.36 (m, 1H), 1.11 (d, J=22.0 Hz, 3H), 1.04 (d, J=6.5 Hz, 3H). 2Protons obscured under the water peak. Chiral SFC: column OX UPC2,isocratic 25% MeOH with 0.1% NH₄OH for 2.5 min. Retention time 0.55 min.LCMS: 520.2 [M+H]⁺.

Example 174(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole174 Step 1: (R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine

The mixture of (2R)-1-(1H-indol-3-yl)propan-2-amine (100 mg, 0.574mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (151 mg, 0.6313mmol), and N,N-diisopropylethylamine (371 mg, 2.87 mmol) in 1,4-dioxane(3.8261 mL) was heated at 50° C. for 6 h. The reaction mixture wascooled to room temperature, diluted with water, and extracted with EtOAc(2×). The combined organics were dried (Na₂SO₄), filtered andconcentrated. The crude product was purified by silica flashchromatography (0-50% iPrOAc/heptane) to give the title compound (89 mg,60.5% yield) as colorless oil. ¹H NMR (Chloroform-d) δ: 8.10-7.92 (m,1H), 7.62-7.56 (m, 1H), 7.33 (dt, J=8.1, 0.9 Hz, 1H), 7.23-7.16 (m, 1H),7.15-7.08 (m, 1H), 7.02-6.98 (m, 1H), 3.21-3.09 (m, 3H), 2.83 (dd,J=6.6, 0.8 Hz, 2H), 1.12 (d, J=6.2 Hz, 3H). LCMS (ESI) m/z 257 [M+H⁺].

Step 2:(1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

The mixture of(2R)-1-(1H-indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (54 mg,0.211 mmol), 2,6-difluoro-4-iodo-benzaldehyde (62 mg, 0.232 mmol) andacetic acid (110 mg, 1.84 mmol) in toluene (1 mL) was heated at 90° C.for 5 h. The mixture was then concentrated. The residue was partitionedbetween EtOAc and sat. NaHCO₃. The aqueous layer was extracted withEtOAc (2×). The combined organics were dried (Na₂SO₄), filtered andconcentrated to give the title compound as a white solid which was usedwithout purification. LCMS (ESI) m/z 507 [M+H⁺].

Step 3: The mixture of(1R,3R)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole(107 mg, 0.211 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (84 mg,0.632 mmol), CuI (16 mg, 0.0843 mmol) and K₂CO₃ (87 mg, 0.632 mmol) inbutyronitrile (1.4 mL) in a microwave vial was purged with N₂ for 5 min,and then sealed and heated at 135° C. for 23 h. The mix was filteredthrough celite, concentrated and purified by prep HPLC to give 174 (51mg, 47% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s,1H), 7.45-7.35 (m, 1H), 7.20 (dt, J=8.0, 0.9 Hz, 1H), 7.05-6.90 (m, 2H),6.71-6.59 (m, 2H), 5.20 (s, 1H), 4.50 (dd, J=47.6, 6.2 Hz, 2H), 3.94 (t,J=5.4 Hz, 2H), 3.57-3.35 (m, 2H), 3.31-3.22 (m, 2H), 2.97 (dt, J=16.8,7.9 Hz, 3H), 2.84 (ddd, J=15.3, 4.9, 1.2 Hz, 1H), 2.77-2.66 (m, 3H),2.64-2.56 (m, 1H), 1.12 (d, J=6.6 Hz, 3H). LCMS (ESI) m/z 512 [M+H⁺].

Example 2863-[(1R,3R)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol286 Step 1: 3-((tert-Butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol

To a stirred solution of 2,2-difluoropropane-1,3-diol (200 mg, 1.78mmol) in THF (4 mL) was added NaH (60% in mineral oil, 71 mg, 1.78 mmol)on an ice bath and the reaction mixture was stirred for 30 minutes.TBDPSCl (490 mg, 1.78 mmol) was added to the reaction mixture drop wise.Then the reaction mixture was warmed up to 20° C. and the stirringcontinued for 3 hours. Water (10 mL) was slowly added to the reactionmixture and the resulting mixture was washed with EtOAc (10 mL*2). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gel columnchromatography (20% petroleum ether in EtOAc) to afford the titlecompound (450 mg, 1.28 mmol, 72% yield) as a light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.71-7.64 (m, 4H), 7.44-7.36 (m, 6H), 3.96-3.84 (m,4H), 1.86 (s, 1H), 1.06 (s, 9H).

Step 2: 3-((tert-Butyl diphenyl si 1 yl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate

To a stirred solution of3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propan-1-ol (From Step 1,400 mg, 1.14 mmol) and 2,6-lutidine (0.39 mL, 3.42 mmol) in DCM (8 mL)was added Tf₂O (0.38 mL, 2.28 mmol) dropwise on an ice bath. Thereaction mixture was stirred at 20° C. for 2 hours. The reaction mixturewas then poured into ice-water (20 mL) slowly, and the mixture wasextracted with DCM (20 mL×2). The combined organic layers were washedwith 1 N HCl (20 mL), saturated NaHCO₃ (20 mL) and brine. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude residue was purified by silica gel column chromatography (10%petroleum ether in EtOAc) to afford the desired product (500 mg, 1.04mmol, 91%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.64(m, 4H), 7.47-7.41 (m, 6H), 4.76 (t, J=7.6 Hz, 2H), 3.89 (t, J=7.6 Hz,2H), 1.08 (s, 9H).

Step 3:(R)—N-(1-(1H-Indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine

A mixture of[3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propyl]trifluoromethanesulfonate(From Step 2, 8.31 g, 17.22 mmol), DIPEA (6.1 mL, 34.44 mmol) and(2R)-1-(1H-indol-3-yl)propan-2-amine (3 g, 17.22 mmol) in dioxane (60mL) was stirred at 90° C. for 12 hours. After being cooled to roomtemperature, the reaction mixture was diluted with water (100 mL) andwas washed with EtOAc (100 mL×2). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by silica gel column chromatography (20% EtOAc in petroleumether) to afford the title compound (7.6 g, 87%) as a yellow oil. LCMS:507.2 [M+H]⁺.

Step 4:(R)-3-((1-(1H-Indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine(From Step 3, 7.6 g, 15 mmol) in THF (100 mL) was added TBAF (1.0 M inTHF, 30 mL, 30 mmol). The reaction mixture was stirred at 25° C. for 4hours and was then diluted with water (200 mL) and was extracted withEtOAc (200 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated. The crude residue was purified bysilica gel column chromatography (70% EtOAc in petroleum ether) toafford the title compound (3.5 g, 87%) as a light yellow oil. LCMS:268.9 [M+H]⁺.

Step 5:3-((1R,3R)-1-(2,6-Difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol

A mixture of(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol(From Step 4, 2 g, 7.45 mmol), HO Ac (1.29 mL, 22.36 mmol) and2,6-difluoro-4-iodo-benzaldehyde (2 g, 7.45 mmol) in toluene (30 mL) wasstirred at 90° C. for 12 hours. After being cooled to room temperature,the reaction mixture was diluted with water (50 mL), washed with EtOAc(50 mL×2). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was purified by silica gelcolumn chromatography (20% petroleum ether in EtOAc) to afford the titlecompound (2.8 g, 73%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ7.53-7.49 (m, 2H), 7.30-7.22 (m, 3H), 7.18-7.13 (m, 2H), 5.25 (s, 1H),3.72-3.68 (m, 3H), 3.24-3.06 (m, 3H), 2.85-2.75 (m, 1H), 2.70-2.66 (m,1H), 1.18 (d, J=6.8 Hz, 3H).

Step 6: A mixture of3-((1R,3R)-1-(2,6-difluoro-4-iodophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol(From Step 5, 1.5 g, 2.89 mmol),2-[3-(fluoromethyl)azetidin-1-yl]ethanol (1.93 g, 14.47 mmol), CuI (1.65g, 8.68 mmol) and K₂CO₃ (1.2 g, 8.68 mmol) in n-PrCN (20 mL) was stirredunder N₂ atmosphere at 135° C. for 3 hours. After being cooled to roomtemperature, the reaction mixture was diluted with water (50 mL), washedwith DCM (50 mL×2). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated. The resulting residue waspurified by reverse phase chromatography (acetonitrile 50-80%/0.05%NH₄OH in water) to afford 286 (170 mg, 11%) as a white solid. ¹H NMR(400 MHz, CD₃OD) δ 7.41 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H),7.03-6.94 (m, 2H), 6.54 (d, J=11.2 Hz, 2H), 5.24 (s, 1H), 4.49 (dd,J=47.6, 6.0 Hz, 2H), 4.00-3.98 (m, 2H), 3.83-3.72 (m, 1H), 3.63-3.45 (m,4H), 3.22-3.13 (m, 3H), 3.02-2.60 (m, 6H), 1.17 (d, J=6.0 Hz, 3H). LCMS:524.1 [M+H]⁺.

Example 303(1R,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[1-(3-fluoropropyl)azetidin-3-yl]oxy-phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole303

Following the procedures of Example 305, 303 was prepared. LCMS: 494.2[M+H]⁺.

Example 304N-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)-1-(3-fluoropropyl)azetidin-3-amine304 Step 1: (R)-1-(1H-Indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine

To a solution of (2R)-1-(1H-indol-3-yl)propan-2-amine (10.0 g, 57.39mmol) in 1,4-dioxane (100 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (13.3 g, 57.39 mmol) and DIPEA (22.2 g, 172.18mmol). The resulting mixture was stirred at 80° C. for 15 hours. Thereaction mixture was concentrated and purified by column chromatographyeluted with 0-30% EtOAc in hexanes to give the title compound (14 g,95.2%) as a light yellow oil. NMR (400 MHz, CDCl₃) δ 8.02 (br. s., 1H),7.60 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H),7.16-7.09 (m, 1H), 7.05 (s, 1H), 3.24-3.11 (m, 3H), 2.84 (d, J=6.4 Hz,2H), 1.14 (d, J=6.4 Hz, 3H).

Step 2:(1R,3R)-1-(4-Bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole

A mixture of(2R)-1-(1H-Indol-3-yl)-N-(2,2,2-trifluoroethyl)propan-2-amine (From step1, 14.0 g, 54.63 mmol), 4-bromo-2,6-difluorobenzaldehyde (11.5 g, 51.9mmol) and acetic acid (6.25 mL, 109.26 mmol) in toluene (150 mL) wasstirred at 90° C. for 16 hours. The reaction mixture was cooled to 25°C., concentrated and purified by silica gel column chromatography (0-5%EtOAc in petroleum ether) to afford the title compound and itscis-isomer (24 g, 95.7% yield) (trans:cis=4:1) as a yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 7.52 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H),7.19-7.05 (m, 4H), 5.69 (s, 0.2H), 5.31 (s, 0.8H), 3.64-3.50 (m, 1H),3.45-3.17 (m, 1H), 3.10-3.06 (m, 1H), 2.98-2.81 (m, 1H), 2.78-2.59 (m,1H), 1.41 (d, J=6.4 Hz, 0.6H), 1.18 (d, J=6.4 Hz, 2.4H).

Step 3: tert-Butyl3-((3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate

A mixture of(1R,3R)-1-(4-bromo-2,6-difluorophenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole(trans:cis=4:1) (From step 2, 23.0 g, 50.08 mmol), Pd₂(dba)₃ (4.59 g,5.01 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (12.9 g, 75.12mmol), Xantphos (5.8 g, 10.02 mmol) and Cs₂CO₃ (48.9 g, 150.25 mmol) in1,4-dioxane (250 mL) was stirred at 115° C. under N₂ atmosphere for 16hours. The reaction mixture was filtered through Celite and the filtratewas concentrated and purified by column chromatography (0-30% EtOAc inpetroleum ether) to afford the title compound (25 g, 90.7% yield)(trans:cis=4:1) as a light brown solid. ¹H NMR (400 MHz, CDCl₃) δ7.56-7.37 (m, 1H), 7.24-7.19 (m, 1H), 7.15-7.06 (m, 2H), 6.04-5.94 (m,2H), 5.57 (s, 0.2H), 5.21 (s, 0.8H), 4.50-4.38 (m, 1H), 4.31-4.21 (m,2H), 3.74-3.72 (m, 2H), 3.61-3.47 (m, 1H), 3.35-3.17 (m, 1H), 3.10-3.07(m, 1H), 3.02-2.78 (m, 1H), 2.77-2.55 (m, 1H), 1.44 (s, 9H), 1.39 (d,J=6.4 Hz, 0.6H), 1.16 (d, J=6.4 Hz, 2.4H).

Step 4:N-(3,5-Difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine

To a solution of tert-butyl3-((3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)amino)azetidine-1-carboxylate(From step 3, 10.0 g, 18.16 mmol) (trans:cis=4:1) in 1,4-dioxane (120mL) was added sulfuric acid (4.87 mL, 90.82 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 0.5 hours. The reaction mixture waspoured into saturated aqueous NaHCO₃ (250 mL) and the mixture wasextracted with EtOAc (200 mL×2). The combined organic layers were driedover Na₂SO₄ and concentrated to give the title compound (8 g, 97.8%yield) (trans:cis=4:1) as a yellow solid. The crude compound was usedfor the next step directly.

Step 5: To a mixture ofN-(3,5-difluoro-4-((1R,3R)-3-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)azetidin-3-amine(From step 4, trans:cis=4:1, 8.0 g, 17.76 mmol) and DIPEA (8.83 mL,53.28 mmol) in DMF (80 mL) was added 1-fluoro-3-iodopropane (3.34 g,17.76 mmol) dropwise. The reaction mixture was stirred at 20° C. for 16hours. The reaction mixture was diluted with EtOAc (400 mL), washed withbrine (200 mL×5). The combined organic layers were dried over Na₂SO₄,filtered, concentrated and purified by column chromatography (10-40%EtOAc in DCM) to afford the desired product (7 g, 77.2% yield) as brownsolid. This product was combined with another batch (12.3 g total) andwas purified by prep-HPLC (Phenomenex Synergi Max-RP 250*80 mm*10 umacetonitrile 50-80/10 mM NH₄HCO₃ in water) to afford 10 g product(trans:cis=4:1, inseparable on HPLC) as a white solid. This product(trans:cis=4:1) was then further purified by SFC (AD(250 mm*30 mm, 10μm) base-EtOH 40%) to afford pure 304 (5.9 g, 59% yield) as a whitesolid. ¹H NMR (400 MHz, CD₃OD) δ 7.40 (d, J=7.6 Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.05-6.91 (m, 2H), 6.09 (d, J=12 Hz, 2H), 5.22 (s, 1H),4.58-4.35 (m, 2H), 4.07-4.02 (m, 1H), 3.77 (t, J=7.6 Hz, 2H), 3.62-3.50(m, 1H), 3.39-3.32 (m, 1H), 3.06-2.90 (m, 4H), 2.66-2.55 (m, 3H),1.87-1.66 (m, 2H), 1.17 (d, J=6.4 Hz, 3H).

Example 305(1R,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole305 Step 1: (R)—N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine

A mixture of (2R)-1-(1H-indol-3-yl)propan-2-amine (4.2 g, 24.1 mmol),2,2-difluoroethyl trifluoromethanesulfonate (5.16 g, 24.1 mmol) anddiisopropylamine (8.41 mL, 48.2 mmol) was heated to 80° C. for 3 hours.The reaction was cooled to room temperature, diluted with iPrOAc (150mL) and was washed with water, brine, dried over sodium sulfate,filtered and concentrated. The crude product was purified by flashcolumn chromatography over silica gel, eluting with 0-5% MeOH/DCM toyield the title compound (5.6 g, 97% yield). ¹H NMR (400 MHz,Chloroform-d) δ 8.03 (s, 1H), 7.63-7.54 (m, 1H), 7.36 (dt, J=8.1, 0.9Hz, 1H), 7.27-7.17 (m, 1H), 7.12 (ddd, J=8.0, 7.1, 1.1 Hz, 1H), 5.78(tdd, J=56.6, 4.7, 4.1 Hz, 1H), 3.11-2.76 (m, 5H), 1.12 (d, J=6.2 Hz,3H); LCMS: 239.15 [M+H]⁺.

Step 2:(1R,3R)-2-(2,2-difluoroethyl)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole

To a solution of(R)—N-(2,2-difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine (5.0 g, 21mmol) and 2,6-difluoro-4-iodobenzaldehyde (5.2 g, 19 mmol) in toluene(70 ml) was added acetic acid (2.4 mL) and the mixture was heated at 90°C. for 20 h under nitrogen atmosphere. The reaction mixture was cooledand concentrated. The residue was dissolved in iPrOAc and was washedwith saturated sodium bicarbonate solution, water, brine, dried oversodium sulfate and concentrated. Purification by flash chromatography(silica gel, 0-15% iPrOAc/heptanes) yielded the title compound (7.8 g,76%) as a 3:1 mixture of trans:cis isomers. LCMS: 489.0 [M+H]⁺. Themixture was carried on to the next step as is.

Step 3: A mixture of(1R,3R)-2-(2,2-difluoroethyl)-1-(2,6-difluoro-4-iodo-phenyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole(8.0 g, 16.4 mmol), 2-[3-(fluoromethyl)azetidin-1-yl]ethanol (2.62 g,19.7 mmol), cuprous iodide (0.94 g, 4.9 mmol), potassium carbonate (4.5g, 32.8 mmol) and butyronitrile (33 mL) was degassed for 5 min and thenheated to 140° C. overnight. The reaction mixture was filtered throughCelite eluting with iPrOAc. The filtrate was concentrated and purifiedby reverse phase HPLC and the cis:trans isomers were separated by chiralSFC to yield 305 (3.77 g, 44% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 10.59(s, 1H), 7.40 (dd, J=7.9, 1.3 Hz, 1H), 7.22-7.14 (m, 1H), 7.04-6.88 (m,2H), 6.66 (d, J=11.1 Hz, 2H), 6.05-5.61 (m, 1H), 5.17 (d, 1.7 Hz, 1H),4.50 (dd, J=47.6, 6.2 Hz, 2H), 3.94 (t, J=5.3 Hz, 2H), 3.41-3.32 (m,2H), 3.15-2.90 (m, 3H), 2.90-2.52 (m, 7H), 1.09 (d, J=6.5 Hz, 3H) LCMS:494.2 [M+H]⁺.

Example 306(1S,3R)-2-(2,2-difluoroethyl)-1-[2,6-difluoro-4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indole306

Following the procedures of Example 305, 306 was prepared. LCMS: 494.2[M+H]⁺.

Example 3403-[(1R,3R)-1-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl]-2,2-difluoro-propan-1-ol340 Step 1:(R)—N-(1-(1H-Indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine

A mixture of (2R)-1-(1H-indol-3-yl)propan-2-amine (29 g, 166.44 mmol),[3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propyl]trifluoromethanesulfonate(80.31 g, 166.44 mmol) and DIPEA (55.01 mL, 332.87 mmol) in 1,4-dioxane(600 mL) was stirred at 90° C. for 12 hours. The reaction mixture wasdiluted in water (600 mL) and was extracted with EtOAc (600 mL*2). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gel columnchromatography (40% EtOAc in petroleum ether) to afford the titlecompound (69 g, 82%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.88 (s, 1H), 7.66 (d, J=7.2 Hz, 4H), 7.60 (d, J=8.0 Hz, 1H), 7.48-7.33(m, 7H), 7.22-7.08 (m, 2H), 7.01 (s, 1H), 3.86-3.79 (m, 2H), 3.23-3.09(m, 3H), 2.86-2.80 (m, 2H), 1.13 (d, J=6.4 Hz, 3H), 1.05 (s, 9H). MS:[M+H]⁺ 507.1.

Step 2:(R)-3-((1-(1H-Indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol

To a stirred solution of(R)—N-(1-(1H-indol-3-yl)propan-2-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-amine(From step 1, 69 g, 136.18 mmol) in THF (690 mL) was added 1 M TBAF(272.35 mL, 272.35 mmol) in THF. The mixture was stirred at 25° C. for 4hours. The reaction mixture was diluted with water (800 mL) and wasextracted with EtOAc (800 mL×3). The combined organic layers wereconcentrated and the crude residue was purified by silica gel columnchromatography (50% EtOAc in petroleum ether) to afford the titlecompound (29 g, 79%) as a light yellow oil.

Step 3:3-((1R,3R)-1-(4-Bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol

A mixture of(R)-3-((1-(1H-indol-3-yl)propan-2-yl)amino)-2,2-difluoropropan-1-ol(From step 2, 20 g, 74.54 mmol), acetic acid (12.91 mL, 223.63 mmol) and4-bromo-2,6-difluorobenzaldehyde (16.47 g, 74.54 mmol) in toluene (400mL) was stirred at 90° C. for 12 hours. The reaction mixture was dilutedwith water (500 mL) and was extracted with EtOAc (500 mL*2). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gel columnchromatography (20% EtOAc in petroleum ether) to afford the titlecompound (24.8 g, 71%, trans/cis=20/1) as a light yellow solid. MS:[M+H]⁺ 470.9.

Step 4: tert-Butyl3-((4-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate

A mixture of3-((1-(4-bromo-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol(From step 3, 24.8 g, 52.62 mmol), Pd₂(dba)₃ (4.82 g, 5.26 mmol),Xantphos (6.09 g, 10.5 2 mmol), Cs₂CO₃ (51.44 g, 157.86 mmol) andtert-butyl 3-aminoazetidine-1-carboxylate (13.59 g, 78.93 mmol) in1,4-dioxane (300 mL) was stirred at 110° C. for 3 hours under N₂atmosphere. The reaction mixture was cooled to 25° C. and was dilutedwith water (500 mL), extracted with EtOAc (500 mL*2). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was purified by silica gel columnchromatography (20% petroleum ether in EtOAc) to afford the titlecompound (20.5 g, 69%, trans/cis=20/1) as a yellow solid. MS: [M+H]⁺563.0.

Step 5:3-((1R,3R)-1-(4-(Azetidin-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol

A solution of tert-butyl3-((4-((1R,3R)-2-(2,2-difluoro-3-hydroxypropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate(From step 4, 20.5 g, 36.44 mmol) in 1,4-dioxane (194 mL) was addedsulfuric acid (19.42 mL, 364.38 mmol) drop wise on an ice bath. Thereaction mixture was stirred at 25° C. for 0.5 hours. The reactionmixture was then poured into saturated aqueous NaHCO₃ solution (800 mL)and was extracted with EtOAc (600 mL*2). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated to affordthe title compound (18 g, crude, trans/cis=20/1) as a yellow solid. Thecrude residue was carried over to the next step directly. MS: [M+H]⁺463.0.

Step 6: A mixture of3-((1R,3R)-1-(4-(azetidin-3-ylamino)-2,6-difluorophenyl)-3-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)-2,2-difluoropropan-1-ol(From step 5, 18 g, 38.92 mmol), DIPEA (19.3 mL, 116.76 mmol) and1-fluoro-3-iodopropane (7.32 g, 38.9 2 mmol) in DMF (180 mL) was stirredat 25° C. for 12 hours. The reaction mixture was diluted with EtOAc (500mL) and was washed with brine (500 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by silica gel column chromatography (10% MeOH inDCM) to afford the desired product (7.1 g, 85% purity) as a yellow oil.The resulting residue was further purified by reverse phasechromatography (acetonitrile 40-75/0.05% NH₃OH in water) and chiral SFC(AD 250 mm*50 mm, 10 um; supercritical CO₂/EtOH(0.1% NH₃H₂O)=40/40 at200 mL/min) to afford 340 (2.85 g, 14%) as a light yellow solid. ¹H NMR(400 MHz, CD₃OD) δ 7.39 (d, J=7.2 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H),7.01-6.93 (m, 2H), 6.11 (d, J=12.0 Hz, 2H), 5.16 (s, 1H), 4.52-4.38 (m,2H), 4.05-4.03 (m, 1H), 3.80-3.74 (m, 3H), 3.63-3.42 (m, 2H), 3.20-3.10(m, 1H), 2.96-2.92 (m, 3H), 2.82-2.71 (m, 1H), 2.64-2.58 (m, 3H),1.81-1.68 (m, 2H), 1.14 (d, J=6.4 Hz, 3H); MS: [M+H]⁺ 523.2.

Example 3653-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol365 Step 1:([3-(tert-Butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine

A mixture of[3-[tert-butyl(diphenyl)silyl]oxy-2,2-difluoro-propyl]trifluoromethanesulfonate(From Example 286, Step 2, 43.22 g, 89.6 mmol), DIPEA (19.5 mL, 112.0mmol) and 2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethylamine (CAS No.:712-08-3, 14.7 g, 74.7 mmol) in dioxane (140 mL) was stirred at 90° C.for 3 hours. The mixture was cooled to room temperature, diluted withEtOAc and washed with water (×2) and brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was purified by silica gelcolumn chromatography (mobile phase: DCM) to afford the title compound(32.8 g, 96%) as a yellow oil. 1H NMR (400 MHz, CDCl₃): δ 7.89 (s, 1H),7.69-7.61 (m, 4H), 7.48-7.34 (m, 6H), 7.26-7.19 (m, 2H), 7.03-7.02 (m,1H), 6.93 (dt, J=2.5, 9.0 Hz, 1H), 3.88-3.78 (m, 2H), 3.22-3.03 (m, 3H),2.84-2.70 (m, 2H), 1.11 (d, J=6.2 Hz, 3H), 1.04 (s, 9H). LCMS: 525.3[M+H]⁺.

Step 2:2-[3-(tert-Butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-1-(2,6-difluoro-4-iodo-phenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline

To a solution of[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine(32.8 g, 62.5 mmol) in toluene (65 mL) was added4-iodo-2,6-difluorobenzaldehyde (20.1 g, 75.0 mmol) and acetic acid (7.2mL, 125.0 mmol). On complete addition the reaction mixture was stirredat 90° C. for 14 hours. The mixture was allowed to cool to roomtemperature, diluted with EtOAc, washed with saturated aqueous NaHCO₃(×3) and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography on silica (mobile phase: toluenein cyclohexane, gradient 10-50%) to afford the title compound (34.9 g,72%) as an off white foam. ¹H NMR (400 MHz, CDCl₃): δ 7.65-7.60 (m, 4H),7.46-7.33 (m, 7H), 7.21-7.08 (m, 4H), 6.90-6.84 (m, 1H), 5.27 (s, 1H),3.99-3.88 (m, 1H), 3.65-3.54 (m, 2H), 3.33-3.20 (m, 1H), 2.93 (ddd,J=1.4, 4.9, 15.2 Hz, 1H), 2.81-2.69 (m, 1H), 2.56-2.51 (m, 1H), 1.14 (d,J=6.6 Hz, 3H), 1.05 (s, 9H). LCMS: 775.2 [M+H]⁺.

Step 3:3-(4-{2-[3-(tert-Butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenylamino)-azetidine-1-carboxylicAcid tert-butyl ester

A mixture of2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-1-(2,6-difluoro-4-iodo-phenyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline(30.8 g, 39.8 mmol), XantPhos (4.60 g, 7.9 mmol), Pd₂(dba)₃ (3.64 g, 4.0mmol), Cs₂CO₃ (25.9 g, 79.4 mmol) and t-butyl3-aminoazetidine-1-carboxylate (10.3 g, 59.6 mmol) in 1,4-dioxane (192mL) was stirred at 115° C. in a sealed vessel under argon for 1.5 hours.The reaction mixture was allowed to cool to room temperature, theresidual solid was removed by filtration through a pad of Celite® andthe filtrate concentrated. The resultant residue was purified by flashchromatography on silica gel (mobile phase: EtOAc in DCM, gradient 0-5%)to afford the title compound (27.9 g, 76%) as a beige foam. ¹H NMR (400MHz, CDCl₃): δ 7.67-7.58 (m, 4H), 7.48-7.32 (m, 6H), 7.15-7.06 (m, 2H),6.88-6.80 (m, 1H), 5.88-5.80 (m, 2H), 5.15 (s, 1H), 4.26-4.09 (m, 2H),4.03-3.91 (m, 2H), 3.69-3.50 (m, 3H), 3.26-3.14 (m, 1H), 2.95-2.90 (m,1H), 2.83-2.70 (m, 1H), 2.50 (dd, J=3.3, 15.1 Hz, 1H), 1.44 (s, 9H),1.13 (d, J=6.5 Hz, 3H), 1.04 (s, 9H). LCMS: 819.4 [M+H]⁺.

Step 4:Azetidin-3-yl-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-amine

A pre-mixed ice cooled solution of cc. sulfuric acid (9.1 mL, 170.2mmol) in dioxane (100 mL) was added slowly to a solution of3-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenylamino)-azetidine-1-carboxylicacid tert-butyl ester (27.9 g, 34.0 mmol) in dioxane (275 mL) undernitrogen at room temperature. On complete addition, the reaction mixturewas for 1 hour at room temperature. EtOAc and water were added and thepH of the aqueous phase adjusted to pH 9 by the addition of solidNa₂CO₃. The organic layer was separated, washed with brine (×3), driedover Na₂SO₄, filtered and concentrated in vacuo to afford the titlecompound (mixture of (R,R) & (S,S) diastereoisomers) as a pale orangefoam (26.6 g, ˜quant). LCMS: 719.4 [M+H]⁺.

Step 5:(4-{2-[3-(tert-Butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-[1-(3-fluoro-propyl)-azetidin-3-yl]-amine

The title compound was prepared fromazetidin-3-yl-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-amine(26.6 g, 34.0 mmol) and 1-iodo-3-fluoropropane (9.60 g, 51.1 mmol; CASNo.; 462-40-8) following the procedure outlined for the preparation ofExample 101. The crude product was purified and purified by silica gelchromatography (mobile phase; dichloromethane/methanol, gradient 0% to5%) to afford the title compound as a pale brown foam (14.9 g, 56%). ¹HNMR (400 MHz, CDCl₃): δ 7.69-7.56 (m, 4H), 7.50 (s, 1H), 7.47-7.30 (m,6H), 7.16-7.01 (m, 2H), 6.87-6.81 (m, 1H), 5.92-5.78 (m, 2H), 5.14 (s,1H), 4.54 (t, J=6.0 Hz, 1H), 4.42 (t, J=6.0 Hz, 1H), 4.18 (d, J=7.0 Hz,1H), 4.06-3.86 (m, 2H), 3.74-3.47 (m, 4H), 3.30-3.10 (m, 1H), 3.00-2.70(m, 3H), 2.56 (t, J=7.2 Hz, 2H), 2.53-2.45 (m, 1H), 1.85-1.50 (m, 3H),1.12 (d, J=6.5 Hz, 3H), 1.04 (s, 9H). LCMS: 779.4 [M+H]⁺.

Step 6:3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-ylamino]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2,2-difluoro-propan-1-ol

To a mixture of(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2,2-difluoro-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenyl)-[1-(3-fluoro-propyl)-azetidin-3-yl]-amine(12.1 g, 15.5 mmol) in THF (150 mL) under argon was added a solution of1M TBAF in THF (23.3 mL) and the reaction mixture was stirred at roomtemperature for 5 hours. The reaction mixture was diluted with EtOAc andwashed with water (×4). The organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel chromatography (mobile phase: 2M ammonia in methanol/TBME,gradient 0.5% to 5%) to afford a mixture of (R,R) and (S,S)3-(1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-ylamino]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2,2-difluoro-propan-1-ol.The pair of diastereoisomers were separated by chiral HPLC (ChiralPakIB, 15% EtOH in heptane+0.1% diethylamine). 365 was the second peakisolated by chiral HPLC: (1.90 g, 23%). Peak 2 rt=15 min. ¹H NMR (400MHz, CDCl₃): δ 7.46 (s, 1H), 7.16-7.08 (m, 2H), 6.86 (dt, J=2.5, 9.0 Hz,1H), 6.08-6.00 (m, 2H), 5.09 (s, 1H), 4.54 (t, J=5.9 Hz, 1H), 4.43 (t,J=5.9 Hz, 1H), 4.38 (d, J=6.7 Hz, 1H), 4.07-3.97 (m, 1H), 3.80-3.56 (m,6H), 3.28-3.16 (m, 1H), 3.11-3.02 (m, 1H), 2.97-2.82 (m, 3H), 2.64-2.55(m, 3H), 1.82-1.67 (m, 2H), 1.16 (d, J=6.5 Hz, 3H). LCMS: 541.4 [M+H]⁺.

Example 3663-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol366

Following the procedures of Example 365, the first peak isolated bychiral HPLC was 366: (1.95 g, 24%). Peak 1 rt=12 min. ¹H NMR (400 MHz,CDCl₃): δ 7.46 (s, 1H), 7.16-7.08 (m, 2H), 6.86 (dt, J=2.5, 9.0 Hz, 1H),6.08-6.00 (m, 2H), 5.09 (s, 1H), 4.54 (t, J=5.9 Hz, 1H), 4.43 (t, J=5.9Hz, 1H), 4.38 (d, J=6.7 Hz, 1H), 4.07-3.97 (m, 1H), 3.80-3.56 (m, 6H),3.28-3.16 (m, 1H), 3.11-3.02 (m, 1H), 2.97-2.82 (m, 3H), 2.64-2.55 (m,3H), 1.82-1.67 (m, 2H), 1.16 (d, J=6.5 Hz, 3H). LCMS: 541.4 [M+H]⁺.

Example 3683-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol368 Step 1:[3-(tert-Butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine

To a solution of 2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethylamine (CASNo.: 712-08-3, 3.61 g, 18.7 mmol)) and DIPEA (4.9 mL, 28.1 mmol) indioxane (43 mL) under argon was added trifluoro-methanesulfonic acid3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl ester,intermediate XX (3.09 g, 9.48 mmol). The resulting mixture was stirredat 90° C. for 6 h. The reaction mixture was partitioned between EtOAcand water. The organic phase was separated and further washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography (mobile phase:dichloromethane/methanol, gradient 0% to 5%) to afford a mixture ofdiastereoisomers of the title compound as a yellow oil (8.0 g, 82%). ¹HNMR (300 MHz, CDCl₃): δ 7.82 (br. s, 1H), 7.68-7.63 (m, 4H), 7.52-7.38(m, 6H), 7.25-7.18 (m, 2H), 7.02-6.98 (m, 1H), 6.92 (dt, J=2.4, 9.1 Hz,1H), 3.82-3.57 (m, 5H), 3.02-2.65 (m, 6H), 1.33 (d, J=22.0 Hz, 3H),1.1-1.0 (m, 9H); LCMS: 521.3 [M+H]⁺.

Step 2:3-(4-{2-[3-(tert-Butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenoxy)-azetidine-1-carboxylicAcid tert-butyl ester

The title compound was prepared from[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-[2-(5-fluoro-1H-indol-3-yl)-1-methyl-ethyl]-amine,intermediate 1a (8 g, 15.3 mmol) and3-(3,5-difluoro-4-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butylester 101c (5.6 g, 18.1 mmol) following the procedure outlined for thepreparation of intermediate 101e. The crude product was purified andpurified by silica gel chromatography (mobile phase: cyclohexane/ethylacetate, gradient 0% to 20%) to afford a mixture of diastereoisomers ofthe title compound as a white foam (8.0 g, 64%). ¹H NMR (300 MHz,CDCl₃): δ 7.65-7.54 (m, 4H), 7.47-7.30 (m, 7H), 7.17-7.08 (m, 2H), 6.84(dt, J=2.4, 9.0 Hz, 1H), 6.23-6.07 (m, 2H), 5.16 (s, 1H), 4.71-4.63 (m,1H), 4.29-4.18 (m, 2H), 3.99-3.88 (m, 2H), 3.79 (dd, J=11.5, 16.8 Hz,1H), 3.64-3.54 (m, 1H), 3.50-3.29 (m, 1H), 3.10-2.83 (m, 2H), 2.69-2.39(m, 2H), 1.54 (s, 3H), 1.46-1.40 (m, 9H), 1.29-0.98 (m, 12H); LCMS:816.5 [M+H]⁺.

Step 3:1-[4-(Azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline

To a mixture of3-(4-{2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl}-3,5-difluoro-phenoxy)-azetidine-1-carboxylicacid tert-butyl ester, intermediate 2a (8.0 g, 9.80 mmol) in dioxane (80mL) under argon at 0° C. was added dropwise a solution of cc. sulfuricacid (2.62 mL, 49.0 mmol) in dioxane (27 mL) and the mixture, protectedfrom light, was allowed to warm to RT and stirred for 3.5 h. Thereaction mixture was diluted with EtOAc and sat. NaHCO₃, stirred for 10min and the layers separated. The organic layer was further washed withsat. NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated invacuo to afford a mixture of diastereoisomers of the title compound as apale yellow foam (7.05 g, ˜quant). ¹H NMR (300 MHz, CDCl₃): ¹H NMR (300MHz, CDCl₃): δ 7.66-7.54 (m, 4H), 7.47-7.30 (m, 7H), 7.17-7.06 (m, 2H),6.84 (dt, J=2.4, 9.0 Hz, 1H), 6.25-6.09 (m, 2H), 5.16 (s, 1H), 4.86-4.76(m, 1H), 3.94-3.65 (m, 3H), 3.63-3.54 (m, 1H), 3.49-3.24 (m, 1H),3.11-2.83 (m, 2H), 2.69-2.39 (m, 2H), 1.54 (s, 3H), 1.27-1.12 (m, 3H),1.11-0.98 (m, 12H); LCMS: 716.4 [M+H]⁺.

Step 4:2-[3-(tert-Butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-yloxy]-phenyl}-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline

The title compound was prepared from1-[4-(azetidin-3-yloxy)-2,6-difluoro-phenyl]-2-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline,intermediate 3a (7.05 g, 9.84 mmol) and 1-iodo-3-fluoropropane (2.77 g,14.7 mmol; CAS No.: 462-40-8) following the procedure outlined for thepreparation of example 101. The crude product was purified by silica gelchromatography (mobile phase: dichloromethane/methanol, gradient 0% to3%) to afford the title compound as a white foam (5.7 g, 75%). LCMS:776.4 [M+H]⁺.

Step 5: racemic3-(1-{2,6-Difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-yloxy]-phenyl}-6-fluoro-3-methyl-1,3,4,9-tetrahydro-beta-carbolin-2-yl)-2-fluoro-2-methyl-propan-1-ol

To a mixture of2-[3-(tert-Butyl-diphenyl-silanyloxy)-2-fluoro-2-methyl-propyl]-1-{2,6-difluoro-4-[1-(3-fluoro-propyl)-azetidin-3-yloxy]-phenyl}-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-beta-carbolineIntermediate 4a (5.17 g, 6.66 mmol) in THF (80 mL) under argon was addeda solution of 1M TBAF in THF (10 mL) and the reaction mixture wasstirred for at RT for 24 h. The reaction mixture was poured into amixture of water and brine and extracted with EtOAc. The aqueous layerwas further extracted with EtOAc and the combined organic layers werefurther washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product was purified by silica gelchromatography (mobile phase: dichloromethane/methanol, gradient 0% to6%) to give two pairs of diastereoisomers (diastereoisomers 1 anddiastereoisomers 2). The pair of diastereoisomers 1 was further purifiedby chiral HPLC (ChiralPak IC, 25% IPA in heptane 0.1% diethylamine).First peak isolated (rt=8.2 mins)=368 isolated as a white solid (467 mg,13%). ¹H NMR (400 MHz, CDCl₃): 7.32 (br s., 1H), 7.17-7.09 (m, 2H),6.89-6.83 (m, 1H), 6.38-6.33 (m, 2H), 5.03 (s, 1H), 4.76-4.69 (m, 1H),4.55 (t, 1H, J=5.9 Hz), 4.47-4.41 (m, 2H), 4.00 (t, 1H, J=4.9 Hz),3.83-3.76 (m, 2H), 3.60 (q, 1H, J=10.3 Hz), 3.46-3.34 (m, 1H), 3.23-3.09(m, 4H), 2.67-2.57 (m, 4H), 1.84-1.69 (m, 2H), 1.14-1.08 (m, 6H); LCMS:538.3 [M+H]⁺.

Example 3693-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol369

Following the procedures of Example 368, the second peak isolated bychiral HPLC (rt=15.5 mins)=369 isolated as a white solid (480 mg,13.5%).

Example 3703-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol370

Following the procedures of Example 368, The pair of diastereoisomers 2was purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane 0.1%diethylamine). The first peak isolated was further purified by chiralHPLC (ChiralPak IA, 25% IPA in heptane 0.1% diethylamine): first peakisolated (rt=8.5 mins)=370 isolated as a white solid (165 mg, 5%). ¹HNMR (400 MHz, CDCl₃): 7.53 (br. s, 1H), 7.16-7.12 (m, 2H), 6.90-6.84 (m,1H), 6.33-6.28 (m, 2H), 5.35 (s, 1H), 4.76-4.68 (m, 1H), 4.55 (t, 1H,J=5.9 Hz), 4.45-4.41 (m, 1H), 3.85-3.54 (m, 6H), 3.16-2.92 (m, 4H), 2.79(t, 1H, J=15.7 Hz), 2.68-2.56 (m, 3H), 1.77 (tdd, J=6.7, 19.3, 19.3 Hz,2H), 1.23-1.15 (m, 6H); LCMS: 538.3 [M+H]⁺.

Example 3713-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol371

Following the procedures of Example 368, the pair of diastereoisomers 2was purified by chiral HPLC (ChiralPak IC, 35% IPA in heptane 0.1%diethylamine). The second peak isolated (rt=14 mins)=371 isolated as awhite solid (180 mg, 5%).

Example 431(R)-3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol431 Step 1:3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-N-(1-(5-fluoro-1H-indol-3-yl)propan-2-yl)-2-methylpropan-1-amine

To a solution of 1-(5-fluoro-1H-indol-3-yl)propan-2-amine (5.30 g, 26.2mmol, 95%, prepared following Yeung, et al, J. Med. Chem. 2010, 53,5155-5164) in 1,4-dioxane (105 mL) cooled with ice bath was addedN,N-diisopropylethylamine (6.85 mL), followed by[3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propyl]trifluoromethanesulfonate(13.80 g, 28.8 mmol) in dioxane (10 mL), following Example 154, step 5.The mixture was heated at 90° C. (bath) for 18 h. The mixture wasconcentrated. Diluted Na₂CO₃ was added. The contents were extracted withDCM (2×). The combined extracts were dried (Na₂SO₄) and concentrated.The crude was purified with flash chromatography (0-50% iPrOAc/heptanewith 1% TEA) to give the product (10.38 g, 76%).

Steps 2-5:N-(4-(2-(3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-2-methylpropyl)-6-fluoro-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidin-3-amine

The compound was prepared in a manner similar to Example 145.

Step 6: racemic3-(1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol

To a solution ofN-[4-[(1R,3R)-2-[3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-2-methyl-propyl]-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]-3,5-difluoro-phenyl]-1-(3-fluoropropyl)azetidin-3-amine(2.231 g, 2.879 mmol) in THF (14.4 mL) was added TBAF in THF (1.0 M, 4.6mL). The mixture was heated at 50° C. for 24 h. The mixture wasconcentrated. Diluted with iPrOAc, the contents were washed with diluteNa₂CO₃ (2×) and brine, dried (Na₂SO₄), and concentrated. The crude waspurified with flash chromatography (0-60% B/A, A: DCM, B: 20% 2M NH₃ inMeOH/DCM). The collected product was subjected to chiral separation. Thestereochemistry assigned to compounds 431-434 in Table 2 are unknown andarbitrary.

Stage 1. Isolation of enantiomers 1 and 4. Enantiomers 2 and 3 remaineda mixture. Chiralpak AD (250×30.0, 5 um), 32.5% isocratic 0.1% NH₄OH inIsopropanol at 150 g/min., UV-254 nm, BPR 100 bar, temp 40° C., cycletime 5 min, total time 200 min. Stage 2: Resolution of enantiomers 2 and3 Chiralpak OX (150×30.0, 5 um), 30% isocratic 0.1% NH4OH in Methanol at150 g/min, UV-250 nm, BPR 100 bar, temp 40° C., cycle time 3 min, totaltime 48 min. Compounds 431-434 were characterized as follows. Enantiomer1: 324.8 mg. ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.19-7.08 (m,2H), 6.85-6.75 (m, 1H), 6.68 (d, J=6.9 Hz, 1H), 6.17-6.06 (m, 2H), 5.01(s, 1H), 4.81 (t, J=5.8 Hz, 1H), 4.51 (t, J=6.1 Hz, 1H), 4.39 (t, J=6.0Hz, 1H), 4.33 (d, J=4.2 Hz, 0H), 3.99-3.87 (m, 1H), 3.82-3.72 (m, 0H),3.67-3.56 (m, 2H), 3.55-3.40 (m, 2H), 3.19-3.05 (m, 1H), 2.95-2.68 (m,4H), 1.74-1.56 (m, 2H), 1.14-0.99 (m, 6H). LCMS: 537.3 [M+H]⁺.Enantiomer 2: 251.7 mg. ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H),7.20-7.07 (m, 2H), 6.86-6.75 (m, 1H), 6.68 (d, J=6.8 Hz, 1H), 6.11 (d,J=12.1 Hz, 2H), 5.01 (s, 1H), 4.81 (t, J=5.8 Hz, 1H), 4.51 (t, J=6.1 Hz,1H), 4.39 (t, J=6.0 Hz, 1H), 4.00-3.87 (m, 1H), 3.68-3.57 (m, 2H),3.55-3.41 (m, 2H), 3.20-3.06 (m, 1H), 2.95-2.69 (m, 4H), 1.73-1.56 (m,2H), 1.17-0.96 (m, 6H). LCMS: 537.3 [M+H]⁺. Enantiomer 3: 105.5 mg. ¹HNMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 7.17-7.08 (m, 2H), 6.84-6.75 (m,1H), 6.67 (d, J=6.8 Hz, 1H), 6.14-6.05 (m, 2H), 4.98 (s, 1H), 4.84 (t,J=5.7 Hz, 1H), 4.51 (t, J=6.0 Hz, 1H), 4.39 (t, J=6.0 Hz, 1H), 3.99-3.87(m, 1H), 3.67-3.57 (m, 2H), 3.57-3.47 (m, 1H), 2.92-2.79 (m, 2H),2.77-2.69 (m, 2H), 1.73-1.56 (m, 2H), 1.13-0.96 (m, 6H). LCMS: 537.3[M+H]⁺. Enantiomer 4: 151.1 mg. ¹H NMR (400 MHz, DMSO-d6) δ 10.55 (s,1H), 7.18-7.07 (m, 2H), 6.84-6.75 (m, 1H), 6.67 (d, J=7.0 Hz, 1H), 6.10(d, J=12.1 Hz, 2H), 4.97 (s, 1H), 4.84 (t, J=5.7 Hz, 1H), 4.51 (t, J=6.1Hz, 1H), 4.39 (t, J=6.1 Hz, 1H), 3.98-3.89 (m, 1H), 3.66-3.58 (m, 2H),3.57-3.48 (m, 1H), 2.93-2.79 (m, 2H), 2.79-2.69 (m, 2H), 1.74-1.57 (m,2H), 1.12-0.96 (m, 6H). LCMS: 537.3 [M+H]⁺.

Example 432(S)-3-((1S,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol432

Following the procedures of Example 431, enantiomer 432 was isolated.

Example 433(S)-3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol433

Following the procedures of Example 431, enantiomer 433 was isolated.

Example 434(R)-3-((1R,3S)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2-fluoro-2-methylpropan-1-ol434

Following the procedures of Example 431, enantiomer 434 was isolated.

Example 901: Breast Cancer Cell ERa High Content Fluorescence ImagingDegradation Assay

MCF7 breast cancer cells were seeded on day 1 at a density of 10,000cells per well in 384 well poly-lysine coated tissue culture plate(Greiner #T-3101-4), in 50 μL/well RPMI (phenol red free), 10% FBS(Charcoal stripped), containing L-glutamine. On day 2, compounds wereprepared at 2 compound source concentrations: 100 μM and 1 μM(ultimately to give 2 overlapping titration curves), in a Labcyte lowdead volume plate, 10 μL/well, and 10 μL of DMSO in designated wells forbackfill, and 5 μM Fulvestrant (control compound) in designated wells.Compounds and controls were dispensed using a Labcyte Echo acousticdispenser to dispense compounds with a predefined serial dilution (1.8×,10 point, in duplicate) and appropriate backfill and control compounds(final total volume transferred was 417.5 nL and compound dispensevolume ranges from 2.5 nL to 417.5 nL; 0.84% DMSO (v/v) final),ultimately producing a concentration range from 0.05 nM to 835 nM. Cellplates were incubated at 37° C., for 4 hours. Fixation andpermeabilization were carried out using a Biotek EL406 plate washer anddispenser as follows. Cells were fixed by addition of 15 μL of 16%paraformaldehyde (Electron Microscopy Sciences #15710-S) directly to the50 μL cell culture medium in each well using the peristaltic pump 5 μLcassette on a Biotek EL406 (final concentration of formaldehyde was 3.7%w/v). Samples were incubated 30 minutes. Well contents was aspirated and50 μL/well of Phosphate Buffered Saline (PBS) containing 0.5% w/v bovineserum albumen, 0.5% v/v Triton X-100 (Antibody Dilution Buffer) wasadded to each well. Samples were incubated for 30 minutes. Well contentswere aspirated and washed 3 times with 100 μL/well of PBS.Immunofluorescence staining of estrogen receptor alpha (ESR1) wascarried out using a Biotek EL406 plate washer and dispenser as follows.The well supernatant was aspirated from the wells and 25 μL/well ofanti-ESR1 mAb (F10) (Santa Cruz sc-8002) diluted 1:1000 in AntibodyDilution Buffer was dispensed. Samples were incubated for 2 hours atroom temperature. Samples were washed 4 times with 100 μL/well of PBS.25 uL/well of secondary antibody solution (Alexafluor 488 conjugateanti-mouse IgG (LifeTechndogies #A21202) diluted 1:1000 and Hoechst33342 1 μg/ml diluted in Antibody Dilution Buffer) were dispensed intoeach well. Samples were incubated for 2 hours at room temperature.Samples were washed 3 times with 100 μL/well of PBS using a BiotekEL406. Quantitative fluorescence imaging of ESR1 was carried out using aCellomics Arrayscan V (Thermo). Fluorescence images of the samples(Channel 1: XF53 Hoechst (DNA stain); Channel 2: XF53 FITC (ESR1 stain))were acquired using a Cellomics VTI Arrayscan using the Bioapplication“Compartmental Analysis” using the auto-exposure (based on DMSO controlwells) setting “peak target percentile” set to 25% target saturation forboth channels. Channel 1 (DNA stain) was used to define the nuclearregion (Circ). Measurements of “Mean_CircAvgIntCh2”, which is theAlexafluor 488 fluorescence intensity (ESR1) within the nuclear region,was measured on a per cell basis and averaged over all the measuredcells. Data analysis was carried out using Genedata Screener Software,with DMSO and 5 nM Fulvestrant treated samples being used to define the0% and 100% changes in ESR1. The “Robust Fit” method was used to definethe inflexion point of curve (EC₅₀) and the plateau of the maximaleffect (Sinf). Degradation data for exemplary Formula I compounds isreported as ER-alpha MCF7 HCS S_(inf)(%) values in Table 1.

Example 902 In Vitro Cell Proliferation Assay

Efficacy of estrogen receptor modulator compounds and chemotherapeuticcompounds are measured by a cell proliferation assay employing thefollowing protocol (Mendoza et al (2002) Cancer Res. 62:5485-5488).

The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneousmethod to determine the number of viable cells in culture based onquantitation of the ATP present, which signals the presence ofmetabolically active cells. The CellTiter-Glo® Assay is designed for usewith multiwell plate formats, making it ideal for automatedhigh-throughput screening (HTS), cell proliferation and cytotoxicityassays. The homogeneous assay procedure involves adding a single reagent(CellTiter-Glo® Reagent) directly to cells cultured inserum-supplemented medium. Cell washing, removal of medium or multiplepipetting steps are not required. The Cell Titer-Glo® Luminescent CellViability Assay, including reagents and protocol are commerciallyavailable (Promega Corp., Madison, Wis., Technical Bulletin TB288).

The assay assesses the ability of compounds to enter cells and inhibitcell proliferation. The assay principle is based on the determination ofthe number of viable cells present by quantitating the ATP present in ahomogenous assay where addition of the Cell Titer-Glo® reagent resultsin cell lysis and generation of a luminescent signal through theluciferase reaction. The luminescent signal is proportional to theamount of ATP present.

Procedure: Day 1—Seed Cell Plates (384-well black, clear bottom,microclear, TC plates with lid from Falcon #353962), Harvest cells, Seedcells at 1000 cells per 54 μl per well into 384 well Cell Plates for 3days assay. Cell Culture Medium: RPMI or DMEM high glucose, 10% FetalBovine Serum, 2 mM L-Glutamine, P/S. Incubate O/N (overnight) at 37° C.,5% CO₂.

Day 2—Add Drug to Cells, Compound Dilution, DMSO Plates (serial 1:2 for9 points). Add 20 μl of compound at 10 mM in the 2nd column of 96 wellplate. Perform serial 1:2 across the plate (10 μl+20 μl 100% DMSO) for atotal of 9 points using Precision Media Plates 96-well conical bottompolypropylene plates from Nunc (cat. #249946) (1:50 dilution). Add 147μl of Media into all wells. Transfer 3 μl of DMSO+compound from eachwell in the DMSO Plate to each corresponding well on Media Plate usingRapidplate® (Caliper, a Perkin-Elmer Co.). For 2 drug combinationstudies, transfer one drug 1.5 μl of DMSO+compound from each well in theDMSO Plate to each corresponding well on Media Plate using Rapidplate.Then, transfer another drug 1.5 μl to the medium plate.

Drug Addition to Cells, Cell Plate (1:10 dilution): Add 6 μl ofmedia+compound directly to cells (54 μl of media on the cells already).Incubate 3 days at 37° C., 5% CO₂ in an incubator that will not beopened often.

Day 5—Develop Plates, Thaw Cell Titer Glo Buffer at room temperature:Remove Cell Plates from 37° C. and equilibrate to room temperature forabout 30 minutes. Add Cell Titer-Glo® Buffer to Cell Titer-Glo®Substrate (bottle to bottle). Add 30 μl Cell Titer-Glo® Reagent (Promegacat. #G7572) to each well of cells. Place on plate shaker for about 30minutes. Read luminescence on Analyst HT Plate Reader (half second perwell).

Cell viability assays and combination assays: Cells were seeded at1000-2000 cells/well in 384-well plates for 16 h. On day two, nineserial 1:2 compound dilutions were made in DMSO in a 96 well plate. Thecompounds were further diluted into growth media using a Rapidplate®robot (Zymark Corp., Hopkinton, Mass.). The diluted compounds were thenadded to quadruplicate wells in 384-well cell plates and incubated at37° C. and 5% CO₂ After 4 days, relative numbers of viable cells weremeasured by luminescence using Cell Titer-Glo® (Promega) according tothe manufacturer's instructions and read on a Wallac Multilabel Reader®(PerkinElmer, Foster City). EC50 values were calculated using Prism®4.0software (GraphPad, San Diego). Drugs in combination assays were dosedstarting at 4×EC₅₀ concentrations. If cases where the EC50 of the drugwas >2.5 μM, the highest concentration used was 10 μM. Estrogen receptormodulator compounds and chemotherapeutic agents were addedsimultaneously or separated by 4 hours (one before the other) in allassays.

An additional exemplary in vitro cell proliferation assay includes thefollowing steps:

1. An aliquot of 100 μl of cell culture containing about 10⁴ cells (seeTable 3 for cell lines and tumor type) in medium was deposited in eachwell of a 384-well, opaque-walled plate.

2. Control wells were prepared containing medium and without cells.

3. The compound was added to the experimental wells and incubated for3-5 days.

4. The plates were equilibrated to room temperature for approximately 30minutes.

5. A volume of CellTiter-Glo® Reagent equal to the volume of cellculture medium present in each well was added.

6. The contents were mixed for 2 minutes on an orbital shaker to inducecell lysis.

7. The plate was incubated at room temperature for 10 minutes tostabilize the luminescence signal.

8. Luminescence was recorded and reported in graphs as RLU=relativeluminescence units.

9. Analyze using the Chou and Talalay combination method and Dose-EffectAnalysis with CalcuSyn® software (Biosoft, Cambridge, UK) in order toobtain a Combination Index.

Alternatively, cells were seeded at optimal density in a 96 well plateand incubated for 4 days in the presence of test compound. Alamar Blue™was subsequently added to the assay medium, and cells were incubated for6 h before reading at 544 nm excitation, 590 nm emission. EC₅₀ valueswere calculated using a sigmoidal dose response curve fit.

Alternatively, Proliferation/Viability was analyzed after 48 hr of drugtreatment using Cell Titer-Glo® reagent (Promega Inc., Madison, Wis.).DMSO treatment was used as control in all viability assays. IC₅₀ valueswere calculated using XL fit software (IDBS, Alameda, Calif.)

The cell lines were obtained from either ATCC (American Type CultureCollection, Manassas, Va.) or DSMZ (Deutsche Sammlung vonMikroorganismen und Zellkulturen GmbH, Braunschweig, Del.). Cells werecultured in RPMI 1640 medium supplemented with 10% fetal bovine serum,100 units/ml penicillin, 2 mM L-glutamine, and 100 mg/ml streptomycin(Life Technology, Grand Island, N.Y.) at 37° C. under 5% CO₂.

Example 903 MCF7 In Vitro Cell Proliferation Assay

MCF7 cells were washed with PBS and plated in RPMI 1640 (Gibco 11835-030[−phenol+glutamine]) and 10% Charcoal Stripped FBS (Gibco 12676-029), inpoly-lysine coated 384 well tissue culture plates (Greiner), at 25,000cells/ml, 40ul/well, and incubated overnight. Compounds were prepared inserial dilution in DMSO at 500-fold the final desired concentrationusing a Biomek-FX and diluted 50-fold in RPMI 1640. The control compoundfulvestrant and negative control dimethylsulfoxide were also prepared ina similar manner. 5 ul of each individual compound concentration andeach control compound was transferred to the cell plate. Fulvestrant wasadded to control wells at a final concentration of 100 nM). DMSO wasadded to negative control wells (0.2% v/v). Five microliters (5 μl) of 1nM Estradiol (in phenol red free RPMI 1640 (Gibco 11835-030) was addedto each well of the cell plate (except no estradiol control wells).Cells were incubated for 72 hours then lysed using Cell TiterGlo reagent(Promega #G7572) 40 ul/well and the luminescence was measured on anEnvision (Perkin Elmer) plate reader. Data were analyzed using GenedataScreener software, using DMSO and Fulvestrant treated samples to define0% and 100% inhibition and EC50 values were calculated using curvefitting using Robust method.

Example 904 ERa Co-Activator Peptide Antagonist Assay

Test compounds were prepared at 1 mM in DMSO and serially diluted in a12 point, 1 to 3-fold titration using a Biomek FX in in 384 well clearV-bottom polypropylene plates (Greiner cat #781280). A 3× compoundintermediate dilution was prepared by mixing 1 mL of each concentrationof the compound serial dilution with 32.3 mL of TR-FRET CoregulatorBuffer E (Life Technologies PV4540). 2 mL of the 3× compoundintermediate dilution was transferred to a 1536-well (AuroraBiotechnologies MaKO 1536 Black Plate, #00028905) using a Biomek FX. ABioraptr Dispenser® (Beckman Coulter) was used to dispense. 2 mL perwell of “3× ERa solution”: 22 nM ERa (human estrogen receptor alpha,GST-tagged ESR1 ligand binding domain, spanning residues S282-V595,either wild-type sequence or containing the mutations: Y537S or D538G)in TR-FRET Coregulator Buffer E containing 7.5 mM dithiothreitol (DTT);and 2 mL of 3× Assay mix (750 nM Fluorescein-PGC1a peptide sequence;Life Technologies PV4421), 12 nM Estradiol, 15 nM Anti-GST Tb-labeledantibody in TR-FRET Coregulator Buffer E (with 7.5 mM DTT). “Noreceptor” control wells received buffer without GST-ERa protein. Plateswere centrifuged at 1800 rpm for 20 seconds in V-spin centrifuge andincubated for 2 hours at room temperature with the plates covered.Measurements were made using a Perkin Elmer EnVision Fluorescence Readerusing TR-FRET setting (Top mirror: Perkin Elmer Lance/DELFIA Dualemission (PE #2100-4160); Excitation filter: Perkin Elmer UV (TFR) 340nm (PE #2100-5010); Emission filtes: Chroma 495 nm/10 nm and 520 nm/25nm (Chroma #PV003 filters for LanthaScreen, 25 mm diameter for EnVision)Excitation light: 100%; Delay: 100 us; Window time: 200; Number ofsequential windows. 1, Time between flashes: 2000 us; Number of flashes:100, Number of flashes (2^(nd) detector): 100. Percentage inhibitionvalues were calculated relative to no compound (DMSO only) controls anda “no ERa controls”. Curve fitting and IC₅₀ calculations were carriedout using Genedata Screener software.

Example 905 In Vivo Mouse Tumor Xenograft Efficacy

Mice: Female severe combined immunodeficiency mice (Fox Chase SCID®,C.B-17/IcrHsd, Harlan) or nude mice (Taconic Farms, Harlan) are 8 to 9weeks old and had a BW range of 15.1 to 21.4 grams on Day 0 of thestudy. The animals are fed ad libitum water (reverse osmosis, 1 ppm Cl)and NIH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crudeprotein, 5.0% crude fat, and 5.0% crude fiber. The mice are housed onirradiated ALPHA-Dri® Bed-o'cobs® Laboratory Animal Bedding in staticmicroisolators on a 12-hour light cycle at 21-22° C. (70-72° F.) and40-60% humidity. PRC specifically complies with the recommendations ofthe Guide for Care and Use of Laboratory Animals with respect torestraint, husbandry, surgical procedures, feed and fluid regulation,and veterinary care. The animal care and use program at PRC isaccredited by the Association for Assessment and Accreditation ofLaboratory Animal Care International (AAALAC), which assures compliancewith accepted standards for the care and use of laboratory animals.

Tumor Implantation: Xenografts are initiated with cancer cells. Cellsare cultured in RPMI1640 medium supplemented with 10% fetal bovineserum, 2 mM glutamine, 100 units/mL penicillin, 100 μg/mL streptomycinsulfate and 25 μg/mL gentamicin. The cells are harvested duringexponential growth and resuspended in phosphate buffered saline (PBS) ata concentration of 5×10⁶ or 10×10⁶ cells/mL depending on the doublingtime of the cell line.

Tumor cells are implanted subcutaneously in the right flank, and tumorgrowth is monitored as the average size approached the target range of100 to 150 mm3. Twenty-one days after tumor implantation, designated asDay 0 of the study, the mice are placed into four groups each consistingof ten mice with individual tumor volumes ranging from 75-172 mm3 andgroup mean tumor volumes from 120-121 mm3 (see Appendix A). Volume iscalculated using the formula:

Tumor Volume (mm³)=(w ² ×l)/2,

where w=width and l=length in mm of a tumor. Tumor weight may beestimated with the assumption that 1 mg is equivalent to 1 mm3 of tumorvolume.

Therapeutic Agents: Estrogen receptor modulator compounds andchemotherapeutic agents are typically prepared from dry powders, storedat room temperature, and protected from light. Drug doses are preparedweekly in 0.5% methylcellulose: 0.2% Tween 80 in deionized water(“Vehicle”) and stored at 4° C. Vehicle (+) is solvent/buffer withethynyl estradiol (ethinyl estradiol, EE2) at 0.1 mg/kg. Vehicle (−) issolvent/buffer without ethynyl estradiol. Doses of compounds areprepared on each day of dosing by diluting an aliquot of the stock withsterile saline (0.9% NaCl). All doses are formulated to deliver thestated mg/kg dosage in a volume of 0.2 mL per 20 grams of body weight(10 mL/kg).

Treatment: All doses are scaled to the body weights of the individualanimals and provided by the route indicated.

Endpoint: Tumor volume is measured in 2 dimensions (length and width),using Ultra Cal IV calipers (Model 54 10 111; Fred V. Fowler Company),as follows: tumor volume (mm³)=(length×width²)×0.5 and analyzed usingExcel version 11.2 (Microsoft Corporation). A linear mixed effect (LME)modeling approach is used to analyze the repeated measurement of tumorvolumes from the same animals over time (Pinheiro J, et al. nlme: linearand nonlinear mixed effects models. R package version 3.1 92. 2009; TanN, et al. Clin. Cancer Res. 2011; 17(6): 1394-1404). This approachaddresses both repeated measurements and modest dropouts due to anynon-treatment-related death of animals before study end. Cubicregression splines are used to fit a nonlinear profile to the timecourses of log 2 tumor volume at each dose level. These nonlinearprofiles are then related to dose within the mixed model. Tumor growthinhibition as a percentage of vehicle control (% TGI) is calculated asthe percentage of the area under the fitted curve (AUC) for therespective dose group per day in relation to the vehicle, using thefollowing formula: % TGI=100×(1−AUC_(dose)/AUC_(veh)) Using thisformula, a TGI value of 100% indicates tumor stasis, a TGI value of >1%but <100% indicates tumor growth delay, and a TGI value of >100%indicates tumor regression. Partial response (PR) for an animal isdefined as a tumor regression of >50% but <100% of the starting tumorvolume. Complete response (CR) was defined as 100% tumor regression(i.e., no measurable tumor) on any day during the study.

Toxicity: Animals are weighed daily for the first five days of the studyand twice weekly thereafter. Animal body weights are measured using anAdventurer Pro® AV812 scale (Ohaus Corporation). Percent weight changeis calculated as follows: body weight change(%)=[(weight_(day new)−weight_(day 0))/weight_(day 0)]×100. The mice areobserved frequently for overt signs of any adverse, treatment-relatedside effects, and clinical signs of toxicity recorded when observed.Acceptable toxicity is defined as a group mean body weight (BW) loss ofless than 20% during the study and not more than one treatment-related(TR) death among ten treated animals. Any dosing regimen that results ingreater toxicity is considered above the maximum tolerated dose (MTD). Adeath is classified as TR if attributable to treatment side effects asevidenced by clinical signs and/or necropsy, or may also be classifiedas TR if due to unknown causes during the dosing period or within 10days of the last dose. A death is classified as NTR if there is noevidence that death was related to treatment side effects.

In-vivo Xenograft Breast Cancer Model; (MCF-7; Tamoxifen-sensitive):Time release pellets containing 0.72 mg 17-f) Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells were grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Trypsinized cells are pelleted andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells are subcutaneously injected (100 μL/animal) on theright flank 2-3 days post pellet implantation. Tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or compound daily for 4 weeks. Tumorvolume and body weight are monitored bi-weekly throughout the study.

In-vivo Xenograft Breast Cancer Model; (Tamoxifen-resistant model):Female nu/nu mice (with supplemental 17-β Estradiol pellets; 0.72 mg; 60day slow release) bearing MCF-7 tumors (mean tumor volume 200 mm³) aretreated with tamoxifen (citrate) by oral gavage. Tumor volume(length×width²/2) and body weight are monitored twice weekly. Followinga significant anti-tumor response in which tumor volume remained static,evident tumor growth is first observed at approximately 100 days oftreatment. At 120 days of treatment, tamoxifen dose is increased.Rapidly growing tumors are deemed tamoxifen resistant and selected forin vivo passage into new host animals. Tumor Fragments (˜100 mm³/animal)from the tamoxifen resistant tumors are subcutaneously implanted intothe right flank of female nu/nu mice (with 17-β Estradiol pellets (0.72mg; 60 day slow release)). Passaged tumors are maintained under constantTamoxifen selection, and tumor volume (length×width²/2) is monitoredweekly. When tumor volume reached ˜150-250 mm³, animals are randomizedinto treatment groups (mean tumor volume 200 mm³) and tamoxifentreatment is terminated. Animals are treated with vehicle or compounddaily for 4 weeks. Tumor volume and body weight are monitored twiceweekly for the duration of the study.

Example 906 Immature Uterine Wet Weight Assay

Female immature CD-IGS rats (21 days old upon arrival) are treated forthree days. Animals are dosed daily for three days. For Antagonist Mode,Vehicle or test compound is administered orally by gavage followed 15minutes later by an oral dose of 0.1 mg/kg Ethynyl Estradiol. ForAgonist Mode, Vehicle or test compound is administered orally by gavage.On the fourth day 24 hours after dose, plasma is collected forpharmacokinetic analysis. Immediately following plasma collection, theanimals are euthanized and the uterus removed and weighed.

Uteri and ovaries from 2 animals per group are fixed in 10% neutralbuffered formalin and paraffin embedded, sectioned and stained for H&E(SDPath). Stained tissues are analyzed and read by a board certifiedpathologist. Uteri and ovaries from 4 animals per group are flash frozenin liquid N₂ for transcriptional analysis, examining a select set ofgenes modulated by the estrogen receptor.

Mice were treated with Formula I compounds(1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole101 and(1R,3R)-1-(2,6-difluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole102, tamoxifen, fulvestrant, AZD9496 (WO 2014/191726, Example 1, page74; U.S. Pat. No. 9,155,727), and two controls; Vehicle and Vehicle plusethynyl estradiol (EE). All compounds were dosed PO, QDx3. Uterine WetWeight (UWW): Body Weight ratios were calculated. The mean EndometrialHeight of Uterine cross sections were measured by histology. Endometrialcell height was measured from the basement membrane to the apical(luminal) surface using a slide viewer at 20× magnification. Obliquelycut areas were avoided. In agonist mode UWW assay, Formula I compounds101 and 102 are antagonists, while AZD9496 is a partial agonist.

Example 907 Adult Uterine Wet Weight-10 Day Assay

Female CD-IGS rats (69 days old, Charles River Laboratories) arepurchased and split into groups. Group 1 is ovariectomized at the vendor(Charles River Laboratories) at 60 days of age and the study is started2 weeks after surgery, while groups 2-8 were intact. Vehicle or testcompound is administered orally for 10 days. Two hours after the 10^(th)and final dose, cardiac punctures are performed and serum is collectedfor pharmacokinetic and estradiol analyses. Immediately following serumcollection, the animals are euthanized and the uterus and ovariesremoved and weighed.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, the descriptions and examples should not be construed aslimiting the scope of the invention. The disclosures of all patent andscientific literature cited herein are expressly incorporated in theirentirety by reference.

We claim:
 1. A compound selected from Formula I:

and stereoisomers, tautomers, or pharmaceutically acceptable saltsthereof, wherein: Y¹ is CR^(b) or N; Y² is —(CH₂)—, —(CH₂CH₂)—, orNR^(a); Y³ is NR^(a) or C(R^(b))₂; where one of Y¹, Y² and Y³ is N orNR^(a); R^(a) is selected from H, C₁-C₆ alkyl, C₂-C₈ alkenyl, propargyl,C₃-C₆ cycloalkyl, and C₃-C₆ heterocyclyl, optionally substituted withone or more groups independently selected from F, Cl, Br, I, CN, OH,OCH₃, and SO₂CH₃; R^(b) is independently selected from H, —O(C₁-C₃alkyl), C₁-C₆ alkyl, C₂-C₈ alkenyl, propargyl, —(C₁-C₆ alkyldiyl)-(C₃-C₆cycloalkyl), C₃-C₆ cycloalkyl, and C₃-C₆ heterocyclyl, optionallysubstituted with one or more groups independently selected from F, Cl,Br, I, CN, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, OH, OCH₃,and SO₂CH₃; R^(c) is selected from H, C₁-C₆ alkyl, allyl, propargyl,optionally substituted with one or more groups independently selectedfrom F, Cl, Br, I, CN, OH, OCH₃, and SO₂CH₃; Z¹ is selected fromCR^(a)R^(b), C(O), and a bond; Cy is selected from C₆-C₂₀ aryldiyl,C₃-C₁₂ carbocyclyldiyl, C₂-C₂₀ heterocyclyldiyl, and C₁-C₂₀heteroaryldiyl; Z² is selected from O, S, NR^(a), C₁-C₆ alkyldiyl, C₁-C₆fluoroalkyldiyl, O—(C₁-C₆ alkyldiyl), O—(C₁-C₆ fluoroalkyldiyl), C(O),and a bond; R¹, R², R³ and R⁴ are independently selected from H, F, Cl,Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃,—CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN,—CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃,—CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃,—N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl,azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino; R⁵ is selected from H, C₁-C₉alkyl, C₃-C₉ cycloalkyl, C₃-C₉ heterocycle, C₆-C₉ aryl, C₆-C₉heteroaryl, —(C₁-C₆ alkyldiyl)-(C₃-C₉ cycloalkyl), —(C₁-C₆alkyldiyl)-(C₃-C₉ heterocycle), C(O)R^(b), C(O)NR^(a), SO₂R^(a), andSO₂NR^(a), optionally substituted with one or more of halogen, CN,OR^(a), N(R^(a))₂, C₁-C₉ alkyl, C₃-C₉ cycloalkyl, C₃-C₉ heterocycle,C₆-C₉ aryl, C₆-C₉ heteroaryl, C(O)R^(b), C(O)NR^(a), SO₂R^(a), andSO₂NR^(a); R⁶ is selected from F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH,—CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F,—CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃,—CH₂CHF₂, —CH₂CH₂F, —CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN, —CO₂H, —COCH₃,—CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CONHCH₂CH₃,—CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃, —N(CH₃)₂,—NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃,—OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃,—S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl,azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino; and m is selected from 0, 1, 2, 3,and 4; where alkyldiyl, fluoroalkyldiyl, aryldiyl, carbocyclyldiyl,heterocyclyldiyl, and heteroaryldiyl are optionally substituted with oneor more groups independently selected from F, Cl, Br, I, —CN, —CH₃,—CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂CH₂OH,—C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH(CH₃)CN, —C(CH₃)₂CN, —CH₂CN, —CH₂NH₂, —CH₂NHSO₂CH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃,—N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃,—NO₂, ═O, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH,—OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂, —S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H,cyclopropyl, cyclopropylamide, cyclobutyl, oxetanyl, azetidinyl,1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino,azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl,pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl,morpholino-methanone, and morpholino.
 2. The compound of claim 1 havingFormula Ia:


3. The compound of claim 2 having Formula Ib:

wherein R⁷ is F, Cl, Br, I, —CN, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂CH(CH₃)₂,—CH₂OH, —CH₂OCH₃, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH,—CH₂CH₂SO₂CH₃, —CH₂OP(O)(OH)₂, —CH₂F, —CHF₂, —CH₂NH₂, —CH₂NHSO₂CH₃,—CH₂NHCH₃, —CH₂N(CH₃)₂, —CF₃, —CH₂CF₃, —CH₂CHF₂, —CH(CH₃)CN, —C(CH₃)₂CN,—CH₂CN, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CONHCH₂CH₃, —CONHCH(CH₃)₂, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NH₂,—NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, —NO₂, ═O, —OH, —OCH₃,—OCH₂CH₃, —OCH₂CH₂OCH₃, —OCH₂CH₂OH, —OCH₂CH₂N(CH₃)₂, —OP(O)(OH)₂,—S(O)₂N(CH₃)₂, —SCH₃, —S(O)₂CH₃, —S(O)₃H, cyclopropyl, cyclopropylamide,oxetanyl, azetidinyl, 1-methylazetidin-3-yl)oxy,N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxyphenyl,pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl,morpholinomethyl, morpholino-methanone, and morpholino; and n isselected from 0, 1, 2, 3, and
 4. 4. The compound of claim 1 havingFormula Ic:


5. The compound of claim 4 having Formula Id:


6. The compound of claim 3 having Formula Ie:

wherein R⁸ is H or —CH₃.
 7. The compound of claim 4 having Formula If:

wherein R⁸ is H or —CH₃.
 8. The compound of claim 1 having Formula Ig:


9. The compound of claim 8 having Formula Ih:


10. The compound of claim 9 having Formula Ii:


11. The compound of claim 10 having Formula Ij:


12. The compound of claim 11 having Formula Ik:


13. The compound of claim 1 wherein Y¹ is CR^(b) and Y³ is NR^(a). 14.The compound of claim 1 wherein Y¹ is N and Y³ is C(R^(b))₂.
 15. Thecompound of claim 1 wherein Y² is —(CH₂)—.
 16. The compound of claim 1wherein Y² is —(CH₂CH₂)—.
 17. The compound of claim 1 wherein R^(c) isH.
 18. The compound of claim 1 wherein Cy is C₆-C₂₀ aryldiyl.
 19. Thecompound of claim 18 wherein aryldiyl is phenyldiyl.
 20. The compound ofclaim 19 wherein phenyldiyl is substituted with one or more F.
 21. Thecompound of claim 1 wherein R¹ and R² are H.
 22. The compound of claim 1wherein R³ is H, and R⁴ is —CH₃.
 23. The compound of claim 1 wherein R⁵is C₁-C₆ fluoroalkyl.
 24. The compound of claim 1 wherein m is
 0. 25.The compound of claim 1 selected from Table
 1. 26. The compound of claim1 selected from Table
 2. 27. A pharmaceutical composition comprised of acompound of claim 1 and a pharmaceutically acceptable carrier, glidant,diluent, or excipient.
 28. The pharmaceutical composition according toclaim 27, further comprising a therapeutic agent.
 29. A process formaking a pharmaceutical composition which comprises combining a compoundof claim 1 with a pharmaceutically acceptable carrier, glidant, diluent,or excipient.
 30. A method of treating an ER-related disease or disorderin a patient comprising administering a therapeutically effective amountof the pharmaceutical composition of claim to a patient with anER-related disease or condition.
 31. The method of claim 30 wherein theER-related disease or disorder is cancer selected from breast cancer,lung cancer, ovarian cancer, endometrial cancer, prostate cancer, anduterine cancer.
 32. The method of claim 31 wherein the cancer is breastcancer.
 33. The method of claim 31 further comprising administering anadditional therapeutic agent selected from an anti-inflammatory agent,an immunomodulatory agent, chemotherapeutic agent, anapoptosis-enhancer, a neurotropic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, ananti-viral agent, an agent for treating blood disorders, an agent fortreating diabetes, and an agent for treating immunodeficiency disorders.34. The method of claim 30 wherein the the pharmaceutical composition isadministered in combination with a therapeutic agent selected frompaclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin,fulvestrant, letrozole, gemcitabine, trastuzumab (HERCEPTIN®,Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim,filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine,and ixabepilone.
 35. The method of claim 30 wherein the thepharmaceutical composition is administered in combination with a CDK 4/6inhibitor.
 36. The method of claim 35 wherein the CDK 4/6 inhibitor isselected from palbociclib (PD-0332991), ribociclib (LEE011) andLY283519.
 37. The method of claim 30 wherein the the pharmaceuticalcomposition is administered in combination with a phosphoinositide3-kinase (PI3K)/mTOR pathway inhibitor selected from everolimus,temsirolimus, BEZ235 (dactolisib), BYL719 (alpelisib), GDC0032(taselisib), BKM120 (buparlisib), BGT226, GDC0068 (ipatasertib),GDC-0980 (apitolisib), GDC0941 (pictilisib), INK128 (MLN0128), INK1117,OSI-027, CC-223, AZD8055, SAR245408, SAR245409, PF04691502, WYE125132,GSK2126458, GSK-2636771, BAY806946, PF-05212384, SF1126, PX866, AMG319,ZSTK474, Cal101 (idelalisib), PWT33597, CU-906, AZD-2014 and CUDC-907.38. A kit for treating a condition mediated by an estrogen receptor,comprising: a) a pharmaceutical composition of claim 27; and b)instructions for use.